JP2017515791A - Mcl-1-modulating compounds for cancer treatment - Google Patents
Mcl-1-modulating compounds for cancer treatment Download PDFInfo
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- JP2017515791A JP2017515791A JP2016554656A JP2016554656A JP2017515791A JP 2017515791 A JP2017515791 A JP 2017515791A JP 2016554656 A JP2016554656 A JP 2016554656A JP 2016554656 A JP2016554656 A JP 2016554656A JP 2017515791 A JP2017515791 A JP 2017515791A
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- pyridin
- methyl
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- cancer
- compound
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Classifications
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/55—Acids; Esters
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本発明は、式(I)の化合物及び癌治療におけるその治療的使用に関する。式中、Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、lは請求項1に定義される通りである。【化1】The present invention relates to compounds of formula (I) and their therapeutic use in the treatment of cancer. Wherein Y1, Y2, Ar1, Ar2, R1, R2, i, j, k, l are as defined in claim 1. [Chemical 1]
Description
本発明は、癌及び細胞増殖障害を治療するための化合物、組成物、及び方法に関し、より詳細には、Mcl−1を調節する化合物の製造及び使用方法に関する。該化合物は、医薬組成物中に含有され、治療薬として使用されてよい。 The present invention relates to compounds, compositions, and methods for treating cancer and cell proliferative disorders, and more particularly to methods of making and using compounds that modulate Mcl-1. The compound may be contained in a pharmaceutical composition and used as a therapeutic agent.
癌は世界における主な死亡原因である。プログラムされた細胞死としても知られているアポトーシスは、形態形成及び組織のホメオスタシス等の様々な生理的過程にも関わる老化又は損傷細胞を取り除くために、多細胞生物が用いる自然な過程である。アポトーシスは、多くのタンパク質が関わる複雑で高度に制御された過程である。これらのタンパク質のいくつかは、細胞死を促進する(「アポトーシス促進性」タンパク質)ものもあれば、細胞死を防ぐ(「抗アポトーシス」タンパク質)ものもある。癌細胞は抗アポトーシス遺伝子を過剰発現させる傾向がある。抗アポトーシス遺伝子の過剰発現は、腫瘍形成、転移性増殖、及び化学療法への抵抗性と関係し、癌細胞を選択的に殺す治療戦略に対する必要性が引き続き存在する。 Cancer is the leading cause of death worldwide. Apoptosis, also known as programmed cell death, is a natural process used by multicellular organisms to remove senescent or damaged cells that are also involved in various physiological processes such as morphogenesis and tissue homeostasis. Apoptosis is a complex and highly controlled process involving many proteins. Some of these proteins promote cell death (“pro-apoptotic” proteins), while others prevent cell death (“anti-apoptotic” proteins). Cancer cells tend to overexpress anti-apoptotic genes. Overexpression of anti-apoptotic genes is associated with tumorigenesis, metastatic growth, and resistance to chemotherapy, and there continues to be a need for therapeutic strategies that selectively kill cancer cells.
より具体的には、アポトーシス制御の欠陥は、造血器腫瘍及び固形腫瘍の両方における癌細胞の化学療法抵抗性にしばしば関係し、Bcl−2ファミリーメンバーの発現異常は、最も頻繁で重要な事象の1つを構成する。これらのタンパク質は、Bcl−2ホモロジードメイン(BHドメインと呼ばれる)を共有する。抗アポトーシスタンパク質(Bcl−2、Bcl−xL...)は、BH1〜BH4ドメインを含有するのに対し、アポトーシス促進性タンパク質は、BH1〜BH3ドメイン(Bax及びBak等のマルチドメインメンバー)又はBH3ドメインのみ(Bim、Puma、Bid、Bad、Noxa、及びHrk等のBH3−only群)を含有する(Adams,J.M.及びCory,S.(2007)Oncogene 26、1324〜1337)。細胞ストレス下でBH3−onlyタンパク質は、抗アポトーシスメンバーの活性を阻害するか又はマルチドメインアポトーシス促進性メンバーを直接活性化させることによってアポトーシスを開始するが、これはあるタンパク質のBH3ドメインと別のタンパク質の疎水性ポケットとの相互作用により媒介される(Shamas−Dinら(2011)Biochimica et Biophysica Acta 1813、508〜520)。 More specifically, defects in apoptotic control are often associated with cancer cell chemoresistance in both hematopoietic and solid tumors, and abnormal expression of Bcl-2 family members is the most frequent and important event. Configure one. These proteins share a Bcl-2 homology domain (referred to as the BH domain). Anti-apoptotic proteins (Bcl-2, Bcl-x L ...) Contain BH1-BH4 domains, whereas pro-apoptotic proteins are BH1-BH3 domains (multidomain members such as Bax and Bak) or Contains only the BH3 domain (BH3-only group such as Bim, Puma, Bid, Bad, Noxa, and Hrk) (Adams, JM and Cory, S. (2007) Oncogene 26, 1324-1337). Under cellular stress, the BH3-only protein initiates apoptosis by inhibiting the activity of anti-apoptotic members or directly activating multidomain pro-apoptotic members, which are one protein BH3 domain and another protein Is mediated by the interaction with the hydrophobic pocket of (Shamas-Din et al. (2011) Biochimica et Biophysica Acta 1813, 508-520).
Bcl−2又はBcl−xL等の抗アポトーシスメンバーの活性を阻害するための絶え間ない努力がなされており、その中でも強力なBH−3類似分子の開発が有望である。これらの分子は、Bcl−2ファミリーの抗アポトーシスタンパク質BH3結合溝に結合し、アポトーシス促進性Bcl−2ファミリーメンバーの解放により細胞死を促進する(Zhang,Linら(2007)Drug Resist.Updat.10、207〜217)。ABT−737(及びABT−737、ABT−263、又はナビトクラックス(Navitoclax)に関連する経口投与可能な化合物)は、Bcl−2及びBcl−xLの抗アポトーシス活性の効率的な阻害を可能にする。これは、造血器腫瘍においては単剤として、固形腫瘍細胞においてはより小さい程度でアポトーシス細胞死を誘導可能なものとして示されている。ABT−737はまた、癌細胞を化学療法に対して感作できる。しかしながら、その活性はMcl−1の不在又は不活性化を条件としており、Mcl−1の高発現及び活性はABT−737応答の不在に関連する(Dai,Y.及びGrant,S.(2007)Cancer Res.67(7)、2908〜2911)。したがって、抗アポトーシスタンパク質Mcl−1の発現及び活性は、ABT−737の活性への大きな障害となる。 Efforts are constantly being made to inhibit the activity of anti-apoptotic members such as Bcl-2 or Bcl-x L , and among them the development of potent BH-3 analogs is promising. These molecules bind to the Bcl-2 family anti-apoptotic protein BH3 binding groove and promote cell death by releasing pro-apoptotic Bcl-2 family members (Zhang, Lin et al. (2007) Drug Resist. Updat. 10). 207-217). ABT-737 (and ABT-737, ABT-263, or an orally administrable compound related to Navitoclax) can efficiently inhibit the anti-apoptotic activity of Bcl-2 and Bcl-x L To. This has been shown to be capable of inducing apoptotic cell death as a single agent in hematopoietic tumors and to a lesser extent in solid tumor cells. ABT-737 can also sensitize cancer cells to chemotherapy. However, its activity is contingent on the absence or inactivation of Mcl-1, and high expression and activity of Mcl-1 is associated with the absence of the ABT-737 response (Dai, Y. and Grant, S. (2007). Cancer Res. 67 (7), 2908-2911). Thus, the expression and activity of the anti-apoptotic protein Mcl-1 is a major obstacle to the activity of ABT-737.
卵巣癌については、発明者らは、Bcl−xL及びMcl−1が協働して腫瘍細胞をアポトーシスから保護するため、それらの同時阻害により化学療法をしていなくても広範なアポトーシスがもたらされるが、Bcl−xL又はMcl−1の下方制御は依然として効果がないことを以前に実証した(Brotinら(2010)Int J Cancer 126、885〜895)。本文脈中、発明者らは更に、Mcl−1の下方制御又は不活性化が、卵巣癌細胞をHA14−1(Simoninら(2009)Mol Cancer Ther 8、3162〜3170)又はABT−737(Simoninら(2013)Apoptosis 18、492〜508)等のBcl−xL標的BH3類似分子に対して感作するために必要とされることを示した。 For ovarian cancer, the inventors have cooperated with Bcl-x L and Mcl-1 to protect tumor cells from apoptosis, and their co-inhibition resulted in extensive apoptosis even without chemotherapy. However, it has previously been demonstrated that down-regulation of Bcl-x L or Mcl-1 is still ineffective (Brotin et al. (2010) Int J Cancer 126, 885-895). In this context, the inventors have further noted that down-regulation or inactivation of Mcl-1 may cause ovarian cancer cells to become HA14-1 (Simonin et al. (2009) Mol Cancer Ther 8, 3162-3170) or ABT-737 (Simonin (2013) Apoptosis 18, 492-508) showed that it is required to sensitize to Bcl-x L target BH3-like molecules.
Mcl−1は3つのBHドメイン(BH1〜BH3)を含有するが、NH2末端において明確に規定されたBH4ドメインを欠いている。Mcl−1は様々な細胞内膜に、特にそのCOOH末端が膜貫通領域を通ってミトコンドリア外膜に局在する。Bcl−2及びBcl−xLと同様に、Mcl−1はBax及び/又はBakと相互に作用してミトコンドリアを介したアポトーシスを阻害可能である。Bcl−2及びBcl−xLとは異なり、Mcl−1の発現はサイトカイン又は成長因子に露出されるとすぐに誘発される。Mcl−1の発現増加は、白血病細胞、肝細胞癌細胞、黒色腫細胞、前立腺癌細胞、及び乳癌細胞を含む広範な種類の腫瘍細胞において細胞生存を促進する。更に、Mcl−1は、体細胞性コピー数の増幅により多くの種類の癌における細胞不死化及び腫瘍形成の一因となる。内部でMcl−1が増幅する癌細胞は、しばしば生存のためにMcl−1に依存する(Beroukhim,R.ら(2010)Nature 463、899〜905)。 Mcl-1 contains three BH domains (BH1~BH3) but lacking a well-defined BH4 domain in the NH 2 -terminal. Mcl-1 localizes to various intracellular membranes, particularly its COOH terminus through the transmembrane region to the outer mitochondrial membrane. Similar to Bcl-2 and Bcl-x L , Mcl-1 can interact with Bax and / or Bak to inhibit apoptosis via mitochondria. Unlike Bcl-2 and Bcl-x L , Mcl-1 expression is triggered as soon as it is exposed to cytokines or growth factors. Increased expression of Mcl-1 promotes cell survival in a wide variety of tumor cells including leukemia cells, hepatocellular carcinoma cells, melanoma cells, prostate cancer cells, and breast cancer cells. In addition, Mcl-1 contributes to cell immortalization and tumor formation in many types of cancer by amplification of somatic copy number. Cancer cells with internal amplification of Mcl-1 are often dependent on Mcl-1 for survival (Berookhim, R. et al. (2010) Nature 463, 899-905).
Mcl−1は、卵巣癌を含む様々な腫瘍細胞内で過剰発現し、更にその発現は化学療法抵抗性に関連している(Shigemasaら(2002)Jpn J Cancer Res 93、542〜550)。重要なことに、Mcl−1の場所はヒト癌において最も頻繁に増幅されるものの1つであり、更に発癌におけるその中心的役割があることを示すため、優先順位の高い治療標的としてその重要性が増している(Beroukhimら(2010)Nature 463、899〜905)。 Mcl-1 is overexpressed in various tumor cells, including ovarian cancer, and its expression is associated with chemotherapy resistance (Shigemasa et al. (2002) Jpn J Cancer Res 93, 542-550). Importantly, the location of Mcl-1 is one of the most frequently amplified in human cancer, and its importance as a high-priority therapeutic target because it shows its central role in carcinogenesis (Berookhim et al. (2010) Nature 463, 899-905).
従って、以下のようなMcl−1を阻害することを目的とした様々な手段を使用して、ABT−737を感作してきた:
− Mcl−1標的siRNA(Linら(2007)Oncogene 26、3972〜3979)、
− Noxa遺伝子導入(Wesargら(2007)Int J Cancer 121、2387〜2394、Lucasら(2012)Clin Cancer Res 18、783〜795)、
− シグナリング経路阻害(Russoら(2013)Biochem Pharmacol 85、927〜936)、又は
− 従来の化学療法(Masonら(2009)Leukemia 23、2034〜2041、Simoninら(2013)Apoptosis 18、492〜508。
Thus, ABT-737 has been sensitized using a variety of means aimed at inhibiting Mcl-1 as follows:
-Mcl-1 target siRNA (Lin et al. (2007) Oncogene 26, 3972-3979),
-Noxa gene transfer (Wesar et al. (2007) Int J Cancer 121, 2387-2394, Lucas et al. (2012) Clin Cancer Res 18, 783-795),
-Signaling pathway inhibition (Russo et al. (2013) Biochem Pharmacol 85, 927-936), or-conventional chemotherapy (Mason et al. (2009) Leukemia 23, 2034-2041, Simonin et al. (2013) Apoptosis 18, 492-508.
これらの戦略はいずれもMcl−1の発現自体の阻害、又はその内因性阻害物質、即ち、Bim、Noxa、若しくはPuma等のBH3−onlyタンパク質の活性化によるMcl−1の抗アポトーシス活性の間接的阻害につながる。従って、前述したように、プラチナ化合物ベースの化学療法は、卵巣癌でMcl−1タンパク質レベルを減少させ、BH3−onlyタンパク質を誘導することができ、ABT−737への感作をもたらす(Simoninら(2009)Molecular Cancer Therapeutics、8(11)、3162〜70、及びSimoninら(2013)Apoptosis 18、492〜508)。しかしながら、部分的には蓄積毒性(従来の化学療法)又は生体内での非効率性(siRNA、遺伝子治療)のため、このような戦略の臨床実務における適用が困難であることから、研究者は特異的且つ強力なMcl−1阻害剤を特定しようとしている。 Both of these strategies are indirect inhibition of the expression of Mcl-1, or its anti-apoptotic activity by activation of its endogenous inhibitor, ie, BH3-only protein such as Bim, Noxa, or Puma. Leads to inhibition. Thus, as described above, platinum compound-based chemotherapy can reduce Mcl-1 protein levels and induce BH3-only protein in ovarian cancer, resulting in sensitization to ABT-737 (Simonin et al. (2009) Molecular Cancer Therapeutics, 8 (11), 3162-70, and Simonin et al. (2013) Apoptosis 18, 492-508). However, researchers have found that this strategy is difficult to apply in clinical practice, due in part to cumulative toxicity (conventional chemotherapy) or in vivo inefficiency (siRNA, gene therapy). We are trying to identify specific and potent Mcl-1 inhibitors.
従って、本発明の目的は、Mcl−1活性を調節、とりわけ阻害するのに有用な代替的化合物を提供することである。 Accordingly, it is an object of the present invention to provide alternative compounds useful for modulating, in particular inhibiting, Mcl-1 activity.
従って、一態様において、本発明は下記構造の様々な化合物又はその薬学的に許容される塩の形態に係り、構成要素は以下で定義される。
本発明の別の目的は、本発明の化合物を含む医薬組成物を提供することであり、当該組成物は、1又は複数の薬学的に許容される賦形剤と、治療有効量の本発明の化合物のうちの少なくとも1つ又はその薬学的に許容許容される塩と、を含む。 Another object of the invention is to provide a pharmaceutical composition comprising a compound of the invention, the composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of the invention. At least one of the compounds or a pharmaceutically acceptable salt thereof.
本発明の別の目的は、式(I)の化合物とBcl−2又はBcl−xL阻害剤との組み合わせを提供することである。 Another object of the present invention is to provide a combination of a compound of formula (I) with a Bcl-2 or Bcl-x L inhibitor.
本発明の別の目的は、癌治療において使用するための式(I)の化合物を提供することである。 Another object of the present invention is to provide compounds of formula (I) for use in cancer therapy.
本発明の別の目的は、式(I)の化合物の調製方法及び式(I)の化合物の調製に有用な式(IIa)又は(IIb)の特定の化合物の調製方法を提供することである。 Another object of the invention is to provide a process for the preparation of compounds of formula (I) and for the preparation of specific compounds of formula (IIa) or (IIb) useful for the preparation of compounds of formula (I). .
式(I)の化合物のこれらの及びその他の目的、特徴、並びに利点は、本開示の以下の発明を実施するための態様において開示される。 These and other objects, features, and advantages of the compounds of formula (I) are disclosed in the following detailed description of the disclosure.
式(I)の化合物
第1の目的において、本発明は、式(I)の化合物及びその薬学的に許容される塩を提供する。
Compounds of Formula (I) In a first object, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof.
式中、
Y1、Y2はそれぞれ独立して、−S−、−C=C−、−N=C−から選択され、但し、Y1、Y2の一方が−S−であれば、もう一方は−N=C−であり;
Ar1、Ar2はそれぞれ独立して、C6〜C10アリール又は5〜7員ヘテロアリールから選択され、当該アリール及びヘテロアリール基は、場合により1〜3個のR3基で置換され、但し:
− Ar1、Ar2は、両方が4−ピリジル、非置換2若しくは3−チオフェニル、3,4−ジメトキシフェニル、又は3,4,5−トリメトキシフェニルから選択される同一の基を表すことはできず、
i及びjは独立して0又は1であり、但し:
− i+j≧1;及び
− Y1、Y2のいずれも−S−でなければ、i+j=2であり;
R1、R2はそれぞれ独立して、C1〜C6アルキル、C6〜C10アリール、(C6〜C10)アリール(C1〜C6)アルキル、(C6〜C10)アリール(C2〜C6)アルケニル、(C6〜C10)アリールカルボニル、(C6〜C10)アリール(C1〜C6)アルキルカルボニル、C(=O)H、COOH、OHから選択され、当該アルキル基は場合によりOHで置換され;
k及びlは独立して0、1であり;
R3はそれぞれ独立して、C1〜C6アルキル、C1〜C6アルコキシ、OH、C(=O)H、(CH2)nCO2H、(CH2)pCN、(CH2)qC(=N(OH))NH2、I、Cl、Br、F、C6〜C10アリール、及び5〜7員ヘテロアリール、(C6〜C10)アリール(C1〜C6)アルキル、(C6〜C10)アリール(C2〜C6)アルケニルから選択され、当該アルキル基は場合によりOHで置換され;
nは0、1、2、3であり;
pは0、1、2、3であり;
qは0、1、2、3であり;
以下の化合物を除く:
2−(ピリジン−3−イル)−5−(5−ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン、
3−(5−メチル−6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン、
3−(6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン。
Where
Y 1 and Y 2 are each independently selected from —S—, —C═C—, and —N═C—, provided that one of Y 1 and Y 2 is —S—. -N = C-;
Ar 1 and Ar 2 are each independently selected from C 6 -C 10 aryl or 5-7 membered heteroaryl, wherein the aryl and heteroaryl groups are optionally substituted with 1 to 3 R 3 groups; However:
-Ar 1 and Ar 2 both represent the same group selected from 4-pyridyl, unsubstituted 2 or 3-thiophenyl, 3,4-dimethoxyphenyl, or 3,4,5-trimethoxyphenyl I ca n’t
i and j are independently 0 or 1, provided that:
I + j ≧ 1; and if neither Y 1 nor Y 2 is −S−, then i + j = 2;
R 1 and R 2 are each independently C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, (C 6 -C 10 ) aryl. (C 2 -C 6 ) alkenyl, (C 6 -C 10 ) arylcarbonyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkylcarbonyl, C (═O) H, COOH, OH The alkyl group is optionally substituted with OH;
k and l are independently 0, 1;
Each R 3 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, C (═O) H, (CH 2 ) n CO 2 H, (CH 2 ) p CN, (CH 2 ) q C (= N (OH )) NH 2, I, Cl, Br, F, C 6 ~C 10 aryl, and 5-7 membered heteroaryl, (C 6 ~C 10) aryl (C 1 -C 6 ) alkyl, (C 6 -C 10) aryl (C 2 -C 6) is selected from alkenyl, the alkyl group optionally substituted with OH;
n is 0, 1, 2, 3;
p is 0, 1, 2, 3;
q is 0, 1, 2, 3;
Excluding the following compounds:
2- (pyridin-3-yl) -5- (5-pyridin-3-yl) -3-styrylpyridin-2-yl) pyridine,
3- (5-methyl-6- (5-methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine,
3- (6- (5-Methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine.
ある種の態様では、Y1及びY2の両方が−N=C−である式(I)の化合物が含まれる。 Certain embodiments include compounds of formula (I) wherein both Y 1 and Y 2 are —N═C—.
特定の態様では、Ar1、Ar2は上記定義の通りであるが、但し、Ar1、Ar2のうち少なくとも1つが5〜7員ヘテロアリールである式(I)の化合物が含まれる。 In a particular embodiment, Ar 1 , Ar 2 are as defined above, provided that at least one of Ar 1 , Ar 2 is a 5-7 membered heteroaryl compound of formula (I).
ある種の態様では、Y1及びY2の両方が−N=C−であれば、Ar1、Ar2のうち少なくとも1つがフェニルである式(I)の化合物が含まれる。 Certain embodiments include compounds of formula (I) wherein if Y 1 and Y 2 are both —N═C—, at least one of Ar 1 and Ar 2 is phenyl.
別の態様では、Ar1及び/又はAr2は、フェニル、ピリジル、ピリミジル、イミダゾリル、ピラゾリル、チオフェニル、トリアゾリル、特にフェニル、3−ピリジル、5−ピリミジル、2−イミダゾリル、3−ピラゾリル、2−チオフェニル、4−トリアゾリルから選択される式(I)の化合物が含まれる。 In another embodiment, Ar 1 and / or Ar 2 is phenyl, pyridyl, pyrimidyl, imidazolyl, pyrazolyl, thiophenyl, triazolyl, in particular phenyl, 3-pyridyl, 5-pyrimidyl, 2-imidazolyl, 3-pyrazolyl, 2-thiophenyl. And compounds of formula (I) selected from 4-triazolyl.
更に別の態様では、Ar1、Ar2のうちの少なくとも1つが窒素原子を含む5〜7員ヘテロアリール、好ましくはピリジル、とりわけ3−ピリジルである式(I)の化合物が含まれる。 Yet another embodiment includes compounds of formula (I) wherein at least one of Ar 1 , Ar 2 is a 5-7 membered heteroaryl containing a nitrogen atom, preferably pyridyl, especially 3-pyridyl.
更に別の態様では、Ar1が3−ピリジル又はフェニルである式(I)の化合物が含まれる。 Yet another embodiment includes compounds of formula (I) wherein Ar 1 is 3-pyridyl or phenyl.
別の態様では、Ar2が3−ピリジル又はフェニルである式(I)の化合物が含まれる。 Another embodiment includes compounds of formula (I) wherein Ar 2 is 3-pyridyl or phenyl.
ある種の態様では、R1、R2が独立してC1〜C6アルキル、(C6〜C10)アリール(C2〜C6)アルケニル、好ましくはメチル及びスチリルから選択される式(I)の化合物が含まれる。 In certain embodiments, R 1 , R 2 are independently selected from C 1 -C 6 alkyl, (C 6 -C 10 ) aryl (C 2 -C 6 ) alkenyl, preferably methyl and styryl. Compounds of I) are included.
別の態様では、R1が5−メチルである式(I)の化合物が含まれる。 Another embodiment includes compounds of formula (I) wherein R 1 is 5-methyl.
更に別の態様では、R2が5−スチリルである式(I)の化合物が含まれる。 Yet another embodiment includes compounds of formula (I) wherein R 2 is 5-styryl.
好ましい態様では、R1が5−メチルであり、且つR2が5−スチリルである式(I)の化合物が含まれる。 Preferred embodiments include compounds of formula (I) wherein R 1 is 5-methyl and R 2 is 5-styryl.
別の態様では、Y1が−S−であり、Y2が−N=C−である式(I)の化合物が含まれる。 Another embodiment includes compounds of formula (I) wherein Y 1 is —S— and Y 2 is —N═C—.
更なるある種の態様では、Ar1が5〜7員ヘテロアリール、特にピリジル、より詳細には3−ピリジルである式(I)の化合物が含まれる。 Certain further embodiments include compounds of formula (I) wherein Ar 1 is a 5-7 membered heteroaryl, especially pyridyl, more particularly 3-pyridyl.
更なるある種の態様では、Ar1が5〜7員ヘテロアリール、特にチオフェニル、より詳細には3−チオフェニルで置換される式(I)の化合物が含まれる。 Certain further embodiments include compounds of formula (I) wherein Ar 1 is substituted with a 5-7 membered heteroaryl, particularly thiophenyl, more particularly 3-thiophenyl.
更なるある種の態様では、Ar2が5〜7員ヘテロアリール,特にピリジル又はチオフェニル、より詳細には3−ピリジル、2−チオフェニル、又は3−チオフェニルである式(I)の化合物が含まれる。 Certain further embodiments include compounds of formula (I) wherein Ar 2 is a 5-7 membered heteroaryl, particularly pyridyl or thiophenyl, more particularly 3-pyridyl, 2-thiophenyl, or 3-thiophenyl. .
その他の態様では、R1がC1〜C6アルキル、(C6〜C10)アリール(C1〜C6)アルキル、特にメチル、イソプロピル、又はナフチル−CH2−から選択される式(I)の化合物が含まれる。 In other embodiments, formula (I) wherein R 1 is selected from C 1 -C 6 alkyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, particularly methyl, isopropyl, or naphthyl-CH 2 —. ).
その他の態様では、薬学的に許容される塩が塩酸塩である式(I)の化合物が含まれる。 Other embodiments include compounds of formula (I) wherein the pharmaceutically acceptable salt is the hydrochloride salt.
その他の態様では、式(Ia)、(Ib)、(Ic)、及び(Id)の化合物から選択される式(I)の化合物が含まれる。 Other embodiments include compounds of formula (I) selected from compounds of formula (Ia), (Ib), (Ic), and (Id).
式中、
X1、X2、X3はそれぞれ独立して、C又はNから選択され、
R1、R2、R3はそれぞれ独立して、上記定義の通りである。
Where
X 1 , X 2 , X 3 are each independently selected from C or N;
R 1 , R 2 and R 3 are each independently as defined above.
更に他の態様では、
− 5,6’−ジ(ピリジン−3−イル)−5’−メチル−3−((E)−スチリル)−2,3’−ビピリジン(MR29072)、
− 5,6’’−ジ(ピリジン−3−イル)−3,5”−ビス−((E)−スチリル)−[2,3’;6’,3”]ターピリジン(MR29075)、
− 3,5’’,5’’−トリメチル−5,6’’−ジフェニル−[2,3’;6’,3’’]−ターピリジン(MR30802)、
− 5’−ブロモ−3’,5−ジメチル−6−(3−メチル−4−ピリジン−3−イルフェニル)−3,2’−ビピリジン(MR30804)、
− 5’−(2−メチル−4−ピリジン−3−イルフェニル)−3’,5−ジメチル−6−(2−メチル−4−ピリジン−3−イルフェニル)−3,2’−ビピリジン(MR30811)、
− 2−(ピリジン−3−イル)−5−(3−メチル−4−ピリジン−3−イルフェニル)−(E)スチリルベンゼン(MR30820)、
− 3−(4−メチル−5−(ピリジン−3−イル)チオフェン−2−イル)ピリジン(MR31327)、
− 3−(4−((ナフタレン−3−イル)メチル)−5−(ピリジン−3−イル)チオフェン−2−イル)ピリジン(MR31328)、
− 3−(4−イソブチル−5−(ピリジン−3−イル)チオフェン−2−イル)ピリジン(MR31330)、
− 2−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)−5−フェニル−3−スチリルピリジン(MR31348)、
− 2−(5−メチル−6−フェニルピリジン−3−イル)−5−(ピリジン−3−イル)−3−スチリルピリジン(MR31349)、
− 5−(3−ベンジルピリジン−2−イル)−2−(5−ベンジルピリジン−3−イル)ピリジン(MR31397)、
及び薬学的に許容されるそれらの塩から選択される式(I)の化合物が含まれる。
In yet another aspect,
5,6′-di (pyridin-3-yl) -5′-methyl-3-((E) -styryl) -2,3′-bipyridine (MR29072),
5,6 ″ -di (pyridin-3-yl) -3,5 ″ -bis-((E) -styryl)-[2,3 ′; 6 ′, 3 ″] terpyridine (MR29075),
3,5 ″, 5 ″ -trimethyl-5,6 ″ -diphenyl- [2,3 ′; 6 ′, 3 ″]-terpyridine (MR30802),
-5'-bromo-3 ', 5-dimethyl-6- (3-methyl-4-pyridin-3-ylphenyl) -3,2'-bipyridine (MR30804),
-5 '-(2-methyl-4-pyridin-3-ylphenyl) -3', 5-dimethyl-6- (2-methyl-4-pyridin-3-ylphenyl) -3,2'-bipyridine ( MR30811),
2- (pyridin-3-yl) -5- (3-methyl-4-pyridin-3-ylphenyl)-(E) styrylbenzene (MR30820),
-3- (4-methyl-5- (pyridin-3-yl) thiophen-2-yl) pyridine (MR31327),
-3- (4-((Naphthalen-3-yl) methyl) -5- (pyridin-3-yl) thiophen-2-yl) pyridine (MR31328),
3- (4-isobutyl-5- (pyridin-3-yl) thiophen-2-yl) pyridine (MR31330),
-2- (5-methyl-6- (pyridin-3-yl) pyridin-3-yl) -5-phenyl-3-styrylpyridine (MR31348),
2- (5-methyl-6-phenylpyridin-3-yl) -5- (pyridin-3-yl) -3-styrylpyridine (MR31349),
-5- (3-benzylpyridin-2-yl) -2- (5-benzylpyridin-3-yl) pyridine (MR31397),
And compounds of formula (I) selected from pharmaceutically acceptable salts thereof.
好ましい態様では、式(I)の化合物は、
− 5,6’−ジ(ピリジン−3−イル)−5’−メチル−3−((E)−スチリル)−2,3’−ビピリジン(MR29072)及びその塩酸塩である。
In a preferred embodiment, the compound of formula (I) is
-5,6'-di (pyridin-3-yl) -5'-methyl-3-((E) -styryl) -2,3'-bipyridine (MR29072) and its hydrochloride.
式(I)の化合物の調製方法
本発明の化合物は、以下に記載される方法を含むがこれらに限定されない当業者に周知の複数の方法により、又は有機合成分野の当業者に公知の標準的な技術を適用してこれらの方法を修正したものにより調製することができる。試薬及び出発物質は市販のものか、又は当業者に周知の技術により容易に合成される。全ての置換基は、別途明記されない限り、前述の定義の通りである。本発明と関連して開示されるすべてのプロセスは、ミリグラム、グラム、マルチグラム、又は商業的工業規模を含む任意の規模で実践されると考えられる。
Methods of Preparation of Compounds of Formula (I) The compounds of the present invention may be prepared by a number of methods well known to those skilled in the art, including but not limited to those described below, or standard methods known to those skilled in the art of organic synthesis. Can be prepared by modifying these methods by applying various techniques. Reagents and starting materials are commercially available or readily synthesized by techniques well known to those skilled in the art. All substituents are as defined above unless otherwise specified. All processes disclosed in connection with the present invention are believed to be practiced on any scale, including milligram, gram, multigram, or commercial industrial scale.
容易に理解されるように、式Iの化合物に存在する官能基は保護基を含んでもよい。保護基は、ヒドロキシル基及びカルボキシル基等の官能基に選択的に付加され、また当該官能基から除去することが可能な化学官能基としてそれ自体知られている。これらの基は、化学化合物中に存在して、このような官能基を、化合物が曝される化学反応条件に対して不活性にする。任意のさまざまな保護基を本発明で用いてもよい。本発明によるその他の好ましい保護基は、Greene,T.W.及びWuts,P.G.M.、「Protective Groups in Organic Synthesis」第2版、Wiley&Sons、1991年、又はP.J.Kocienski、「Protecting Groups」、第3版、Thieme、シュトゥットガルト、ニューヨーク、2004年に見出すことができる。 As will be readily appreciated, the functional groups present in compounds of formula I may include protecting groups. Protecting groups are known per se as chemical functional groups that can be selectively added to and removed from functional groups such as hydroxyl and carboxyl groups. These groups are present in the chemical compound, rendering such functional groups inert to the chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be used in the present invention. Other preferred protecting groups according to the present invention are described in Greene, T .; W. And Wuts, P .; G. M.M. "Protective Groups in Organic Synthesis", 2nd edition, Wiley & Sons, 1991, or P.O. J. et al. Kocienski, “Protecting Groups”, 3rd edition, Thiem, Stuttgart, New York, 2004.
このようにして調製された化合物は、従来の手段によって反応混合物から回収できる。例えば、化合物は抽出後に溶媒混合液から蒸留してもよく、あるいは必要であれば、溶媒混合液から蒸留した後に残渣を水に注ぎ、その後、水不混和性有機溶媒を用いて抽出し、溶媒混合物から蒸留してもよい。加えて、所望であれば、生成物は更に、再結晶化、沈殿反応、又は様々なクロマトグラフィー技術、とりわけカラムクロマトグラフィー若しくは分取薄層クロマトグラフィー、特に高速液体クロマトグラフィー(HPLC)等の様々な公知の技術によって精製され得る。 The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compound may be distilled from the solvent mixture after extraction, or if necessary, after distillation from the solvent mixture, the residue is poured into water and then extracted with a water-immiscible organic solvent, It may be distilled from the mixture. In addition, if desired, the product can be further recrystallized, precipitated, or various chromatographic techniques such as column chromatography or preparative thin layer chromatography, especially high performance liquid chromatography (HPLC). Can be purified by known techniques.
別の目的においては、本発明は、
i)鈴木−宮浦カップリングに従って、パラジウム(Pd0)触媒及び塩基の存在下において、化合物(IIa)をAr2B(OH)2と反応させ、式中、Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、lは上記定義の通りであり、Hal2はI又はBrである工程と、場合により、
ii)得られた式(I)の化合物を回収する工程と、を含む、本明細書に定義される式(I)の化合物の調製方法に関する。
In another object, the present invention provides:
i) Compound (IIa) is reacted with Ar 2 B (OH) 2 in the presence of a palladium (Pd 0 ) catalyst and a base according to the Suzuki-Miyaura coupling, wherein Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , i, j, k, l are as defined above, Hal 2 is I or Br, and optionally
ii) recovering the resulting compound of formula (I), and a process for preparing a compound of formula (I) as defined herein.
更なる態様では、式(IIa)の化合物は、
i)鈴木−宮浦カップリングに従って、パラジウム(Pd0)触媒及び塩基の存在下において、式(IV)の化合物をボロン酸(III)と反応させ、式中、Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、lは上記定義の通りであり、Hal1はI又はBrであり、Hal2はClである工程と、場合により、
ii)得られた式(IIa)の化合物を回収する工程と、を含む方法に従って調製される。
In a further aspect, the compound of formula (IIa) is
i) The compound of formula (IV) is reacted with boronic acid (III) in the presence of a palladium (Pd 0 ) catalyst and a base according to the Suzuki-Miyaura coupling, wherein Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , i, j, k, l are as defined above, Hal 1 is I or Br, and Hal 2 is Cl.
and ii) recovering the resulting compound of formula (IIa).
別の態様において、本発明は、
i)鈴木−宮浦カップリングに従って、パラジウム(Pd0)触媒及び塩基の存在下において、化合物(IIb)をAr2B(OH)2と反応させ、式中、Y1、Y2、Ar1、Ar2、R1、R2、k、lは上記定義の通りであり、Ar1及びAr2は同一であり、Hal2はI又はBrである工程と、場合により、
ii)得られた式(I)の化合物を回収する工程と、を含む、上記定義の式(I)の化合物の調製方法に関する。
In another aspect, the invention provides:
i) According to Suzuki-Miyaura coupling, compound (IIb) is reacted with Ar 2 B (OH) 2 in the presence of a palladium (Pd 0 ) catalyst and a base, wherein Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , k, and l are as defined above, Ar 1 and Ar 2 are the same, and Hal 2 is I or Br.
ii) recovering the resulting compound of formula (I), and a process for preparing a compound of formula (I) as defined above.
式(I)の化合物の調製に有用な合成中間体
更なる目的において、本発明は式(IIa)の化合物に関する。
Synthetic Intermediates Useful for the Preparation of Compounds of Formula (I) In a further object, the present invention relates to compounds of formula (IIa).
式中、
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、lは上記定義の通りであり、
Hal2はI、Br、又はClである。
Where
Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , i, j, k, l are as defined above,
Hal 2 is I, Br, or Cl.
一例として、式(IIa)の化合物は、
− 2−(6−ブロモ−5−メチルピリジン−3−イル)−5−(5−クロロ−1−メチル−1H−イミダゾール−2−イル)−3−スチリルピリジン(MR31352)、
− 2−ブロモ−3−メチル−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン(MR31360)、
− 5−(6−(6−ブロモ−5−メチルピリジン−3−イル)−5−スチリルピリジン−3−イル)ピリミジン(MR31362)、
− 3−(6−(6−ブロモ−5−メチルピリジン−3−イル)−5−スチリルピリジン−3−イル)フェノール(MR31377)、
− 2−(3−(6−(6−ブロモ−5−メチルピリジン−3−イル)−5−スチリルピリジン−3−イル)フェニル)アセトニトリル(MR31380)
から選択されてよい。
As an example, the compound of formula (IIa) is
2- (6-bromo-5-methylpyridin-3-yl) -5- (5-chloro-1-methyl-1H-imidazol-2-yl) -3-styrylpyridine (MR31352),
-2-bromo-3-methyl-5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) pyridine (MR31360),
-5- (6- (6-Bromo-5-methylpyridin-3-yl) -5-styrylpyridin-3-yl) pyrimidine (MR31362),
3- (6- (6-Bromo-5-methylpyridin-3-yl) -5-styrylpyridin-3-yl) phenol (MR31377),
2- (3- (6- (6- (6-Bromo-5-methylpyridin-3-yl) -5-styrylpyridin-3-yl) phenyl) acetonitrile (MR31380)
May be selected.
更なる目的においては、本発明は、式(IIb)の化合物に関する。 In a further object, the present invention relates to a compound of formula (IIb).
式中、
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、lは上記定義の通りであり、
Hal2はI又はBrである。
Where
Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , i, j, k, l are as defined above,
Hal 2 is I or Br.
一例として、式(IIb)の化合物は、
− 5−ブロモ−2−(6−ブロモ−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR29061)、
− 5−ブロモ−2−(6−ヨード−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR29069)
から選択されてよい。
As an example, the compound of formula (IIb) is
-5-bromo-2- (6-bromo-5-methylpyridin-3-yl) -3-styrylpyridine (MR29061),
5-Bromo-2- (6-iodo-5-methylpyridin-3-yl) -3-styrylpyridine (MR29069)
May be selected.
医薬組成物
別の目的において、本発明は式(I)の化合物及びその薬学的に許容される塩を含む医薬組成物に関する。
Pharmaceutical Compositions In another object, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) and pharmaceutically acceptable salts thereof.
式中、
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、及びlは上記定義の通りであり、
少なくとも1種の薬剤として許容される賦形剤又はキャリアと混合された以下の化合物を除く。
− 2−(ピリジン−3−イル)−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン、
− 3−(5−メチル−6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン、
− 3−(6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン。
Where
Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , i, j, k, and l are as defined above,
Exclude the following compounds mixed with at least one pharmaceutically acceptable excipient or carrier.
-2- (pyridin-3-yl) -5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) pyridine,
-3- (5-methyl-6- (5-methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine,
3- (6- (5-Methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine.
特定の態様では、以下の式(I)の化合物を除く上記定義の医薬組成物が含まれる。 A particular embodiment includes a pharmaceutical composition as defined above excluding the following compound of formula (I):
− 3,3’−ジメチル−2,5”−ジピリジン−3−イル−[2,5’;2’,5”]ターピリジン、
− 3,3’,3”−トリメチル−2,5”−ジピリジン−3−イル−[2,5’;2’,5”]ターピリジン、
− 3,3’,3”,3”’−テトラメチル−2,5”−ジピリジン−3−イル−[2,5’;2’,5”;2”,5”’]クアテルピリジン、
− 3’,3’’,3’’’−トリメチル−2,5’’−ジピリジン−3−イル−[2,5’;2’,5’’;2’’,5’’’]クアテルピリジン
3,3 ′, 3 ″ -trimethyl-2,5 ″ -dipyridin-3-yl- [2,5 ′; 2 ′, 5 ″] terpyridine,
3,3 ′, 3 ″, 3 ″ ′-tetramethyl-2,5 ″ -dipyridin-3-yl- [2,5 ′; 2 ′, 5 ″; 2 ″, 5 ″ ′] quaterpyridine,
3 ′, 3 ″, 3 ′ ″-trimethyl-2,5 ″ -dipyridin-3-yl- [2,5 ′; 2 ′, 5 ″; 2 ″, 5 ′ ″] qua Terpyridine
特定の態様では、式(I)の化合物が上記定義の通りであり、但し、Y1、Y2の両方がN=Cであるか又はY1、Y2の一方がN=Cであり、他方がC=Cであり、Ar1、Ar2の両方がピリジニルである場合、R1、R2のうちの少なくとも1つが存在し、H又はCH3とは異なる、医薬組成物が含まれる。 In a particular embodiment, the compound of formula (I) is as defined above, provided that both Y 1 and Y 2 are N═C or one of Y 1 and Y 2 is N═C; When the other is C═C and both Ar 1 and Ar 2 are pyridinyl, pharmaceutical compositions in which at least one of R 1 , R 2 is present and different from H or CH 3 are included.
他の態様では、Bcl−xL阻害剤、特にHA14−1、ABT−737、又はABT−263等のBH3類似阻害剤を更に含む医薬組成物が含まれる。 In other embodiments, a pharmaceutical composition further comprising a Bcl-x L inhibitor, particularly a BH3-like inhibitor such as HA14-1, ABT-737, or ABT-263.
当業者に明らかであるように、当該医薬組成物の特定の配合は、治療する癌の種類に基づいて選択可能である。本発明の組成物は、患者に投与するために、その安定性を改善し、且つ/又は生体内での制御放出若しくは持続放出を提供する物質を用いて配合可能である。 As will be apparent to those skilled in the art, the particular formulation of the pharmaceutical composition can be selected based on the type of cancer being treated. The compositions of the invention can be formulated with substances that improve their stability and / or provide controlled or sustained release in vivo for administration to a patient.
これらの医薬組成物は、製薬分野において周知の方法で調製可能であり、局所療法又は全身療法のどちらが所望されるか、また治療部位に応じてさまざまな経路で投与可能である。 These pharmaceutical compositions can be prepared by methods well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic therapy is desired and on the treatment site.
投与は、局所(皮膚、目、並びに鼻孔内、膣、及び直腸送達を含む粘膜への投与を含む)、肺(例えば、ネブライザによるものを含む粉末又はエアゾールの吸入又は吹入れによる、気管内、鼻孔内、表皮、及び経皮)、目、口腔、又は非経口であってよい。目への送達方法としては、局所投与(点眼薬)、結膜下、眼周囲、又は硝子体内への注射又はバルーンカテーテル若しくは外科手術により結膜嚢に配置された眼科用挿入物による導入を挙げることができる。非経口投与としては、静脈内、動脈内、皮下、腹腔内、若しくは筋肉への注射若しくは注入、又は頭蓋内、例えば、くも膜下若しくは脳室内投与が挙げられる。 Administration is topical (including administration to the skin, eyes, and mucosa including intranasal, vaginal, and rectal delivery), lungs (eg, by trachea, by inhalation or insufflation of powders or aerosols, including through nebulizers, May be intranasal, epidermal, and transdermal), eye, buccal, or parenteral. Delivery methods to the eye include topical administration (eye drops), subconjunctival, periocular or intravitreal injection, or introduction with an ophthalmic insert placed in the conjunctival sac by a balloon catheter or surgery. it can. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial, eg, intrathecal or intraventricular administration.
医薬組成物は、当該技術分野において公知の手順を用いることによって患者への投与後、活性成分の急速放出、持続放出、又は遅延放出を提供するように配合可能である。 The pharmaceutical composition can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a patient by using procedures known in the art.
医薬組成物は通常、薬学的に許容される無機又は有機のキャリア、防腐剤、可溶化剤、安定剤、湿潤剤、乳化剤、甘味剤、着色剤、矯味剤、浸透圧を変えるための塩、緩衝液、マスキング剤、又は酸化防止剤を含む。医薬組成物は、その他の治療的価値のある物質を更に含有する。これらの成分は、投与方法及び投与経路に基づいて選択される。薬剤成分並びに薬物調合において使用するために好適な製薬補助薬は、Remington’s Pharmaceutical Sciences(E.W.Martin)に記載されている。 Pharmaceutical compositions are usually pharmaceutically acceptable inorganic or organic carriers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, Contains buffer, masking agent, or antioxidant. The pharmaceutical composition further contains other therapeutically valuable substances. These components are selected based on the administration method and administration route. Pharmaceutical ingredients as well as pharmaceutical adjuvants suitable for use in drug formulation are described in Remington's Pharmaceutical Sciences (EW Martin).
本発明の化合物の治療用量は、例えば、治療を行う特定の用途、化合物の投与方法、患者の健康状態及び疾患、並びに担当医の判断に応じてさまざまでありうる。医薬組成物中の本発明の化合物の比率又は濃度は、用量、化学的特徴(例えば、疎水性)、及び投与経路を含むいくつかの要因に応じてさまざまでありうる。 The therapeutic dose of the compounds of the present invention can vary depending on, for example, the particular application for which treatment is being performed, the method of administration of the compound, the patient's health and disease, and the judgment of the attending physician. The ratio or concentration of a compound of the invention in a pharmaceutical composition can vary depending on a number of factors including dosage, chemical characteristics (eg, hydrophobicity), and route of administration.
組み合わせ
いくつかの実施形態では、本発明の化合物は、少なくとも1種の第2の治療薬を併用してよい。
Combinations In some embodiments, the compounds of the invention may be used in combination with at least one second therapeutic agent.
従って、化合物は、細胞毒性薬又は癌化学療法剤等の別の治療薬とともに投与されてよい。2種以上の治療薬の併用投与は、治療薬が治療効果を発揮する期間が重なっていれば、同一期間中に又は同一経路によって治療薬が同時に投与されることを必要としない。同時投与又は連続投与は、その投与を異なる日数又は週数で考慮される。 Thus, the compound may be administered with another therapeutic agent such as a cytotoxic agent or a cancer chemotherapeutic agent. The combined administration of two or more therapeutic agents does not require that the therapeutic agents be administered simultaneously during the same period or by the same route, as long as the periods in which the therapeutic agents exhibit therapeutic effects overlap. Simultaneous or sequential administration is considered on different days or weeks.
本化合物と組み合わせて投与されてよいその他の有用な治療としては、Bcl−2ファミリーの他のメンバーを標的とする薬剤が挙げられる。抗Bcl−2剤は、Bcl−2の活性を調節する任意の薬剤であってよく、抗Bcl−2オリゴヌクレオチド、抗Bcl−2抗体、及び小分子阻害剤を挙げることができる。例示的な小分子阻害剤としては、ゴシポール及びゴシポール類似体(例えば、AT−101)、ベンゼンスルホニル誘導体、すなわちTW37、アポゴシポール誘導体、即ち、サブトクラックス、ABT−199、ABT−737及び経口投与可能な類似体、AGT−263を含むABT系の化合物、オバトクラックス、並びにHA14−1が挙げられる。 Other useful treatments that may be administered in combination with the present compounds include agents that target other members of the Bcl-2 family. The anti-Bcl-2 agent may be any agent that modulates the activity of Bcl-2, and may include anti-Bcl-2 oligonucleotides, anti-Bcl-2 antibodies, and small molecule inhibitors. Exemplary small molecule inhibitors include gossypol and gossypol analogs (eg, AT-101), benzenesulfonyl derivatives, ie TW37, apogossypol derivatives, ie subtox, ABT-199, ABT-737 and oral administration. Possible analogs, ABT-based compounds including AGT-263, Obatocrax, and HA14-1.
本発明は好ましくは、Bcl−xL阻害剤、特にBH3類似阻害剤、例えば、HA14−1、ABT−737、又はABT−263と組み合わせた式(I)の化合物を含む組み合わせに関する。 The present invention preferably relates to a combination comprising a compound of formula (I) in combination with a Bcl-x L inhibitor, in particular a BH3 analogue inhibitor, such as HA14-1, ABT-737 or ABT-263.
癌治療において使用するための式(I)の化合物
本明細書に開示される化合物及び組成物は、概して、癌治療にさまざまに役立つ。
Compounds of Formula (I) for Use in Cancer Treatment The compounds and compositions disclosed herein generally serve a variety of cancer treatments.
従って、更なる目的において、本発明は、癌、とりわけMcl−1の調節に反応する癌の治療において使用する式(I)の化合物及びその薬学的に許容される塩に関する。 Thus, in a further object, the present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts for use in the treatment of cancer, in particular cancer responsive to modulation of Mcl-1.
式中、
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、及びlは、上記定義の通りである。
Where
Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , i, j, k, and l are as defined above.
本発明の治療方法の影響を受けやすい癌は、Mcl−1の調節に反応する癌でありえ、従って、Mcl−1の誤調節(例えば、過剰発現又は変化した結合若しくは活性)に関連する任意の形態の癌は本発明の範囲内である。 A cancer susceptible to the therapeutic methods of the invention can be a cancer that is responsive to modulation of Mcl-1, and thus any of those associated with Mcl-1 misregulation (eg, overexpression or altered binding or activity). Forms of cancer are within the scope of the present invention.
癌又は腫瘍性疾患としては、例えば、乳癌、骨髄腫、白血病、及びリンパ腫(例えば、バーキットリンパ腫、非ホジキンリンパ腫、ホジキンリンパ腫、及び急性T細胞白血病)等の血液癌、脳腫瘍、例えば、星状細胞腫又は膠芽腫を含む神経膠腫等の神経腫瘍、黒色腫、肺癌、頭頸部癌、甲状腺癌、胃癌、結腸癌又は直腸癌等の胃腸腫瘍、肝臓癌、膵臓癌、卵巣癌、膣癌、外陰癌、子宮内膜癌、膀胱癌、腎臓癌、睾丸癌、前立腺癌、又は陰茎癌等の泌尿生殖器腫瘍、骨腫瘍、血管性腫瘍、並びに基底細胞癌、扁平上皮細胞癌、及び黒色腫等の皮膚癌が挙げられるが、これらに限定されない。 Cancers or neoplastic diseases include, for example, blood cancers such as breast cancer, myeloma, leukemia, and lymphoma (eg, Burkitt lymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma, and acute T-cell leukemia), brain tumors, eg, stellate Nerve tumors such as glioma including cell tumor or glioblastoma, melanoma, lung cancer, head and neck cancer, thyroid cancer, gastrointestinal tumor such as stomach cancer, colon cancer or rectal cancer, liver cancer, pancreatic cancer, ovarian cancer, vagina Cancer, vulvar cancer, endometrial cancer, bladder cancer, kidney cancer, testicular cancer, prostate cancer, or urogenital tumors such as penile cancer, bone tumor, vascular tumor, and basal cell cancer, squamous cell carcinoma, and black Examples include, but are not limited to, skin cancers such as tumors.
好ましくは、式(I)の化合物は、リンパ腫、白血病、多発性骨髄腫等の造血器腫瘍、並びに卵巣癌、中皮腫、黒色腫、膵臓癌、肺癌、乳癌、腎臓癌、及び肝臓癌等の固形腫瘍の治療に有用である。造血器腫瘍は、Bcl−xLを標的とする戦略に反応するようにMcl−1中毒(addicted to Mcl−1)であるものとして記載されている(Daiら(2007)Cancer Res.,67(7),2908〜11;Yeciesら(2010)Blood,115(16),3304〜13)。 Preferably, the compound of formula (I) is a hematopoietic tumor such as lymphoma, leukemia, multiple myeloma, and ovarian cancer, mesothelioma, melanoma, pancreatic cancer, lung cancer, breast cancer, kidney cancer, liver cancer, etc. It is useful for the treatment of solid tumors. Hematopoietic tumors have been described as being Mcl-1 addicted to respond to strategies targeting Bcl-x L (Dai et al. (2007) Cancer Res., 67 ( 7), 2908-11; Yecies et al. (2010) Blood, 115 (16), 3304-13).
特定の態様では、式(I)の化合物は好ましくは、Bcl−xL阻害剤、特にBH3類似阻害剤、例えば、
− 2−アミノ−6−ブロモ−α−シアノ−3−(エトキシカルボニル)−4H−1−ベンゾピラン−4−酢酸エチルエステル(HA14−1とも呼ばれる)、
−4−[4−[[2−(4−クロロフェニル)フェニル]メチル]ピペラジン−1−イル]−N−[4−[[(2R)−4−(ジメチルアミノ)−1−フェニルスルファニルブタン−2−イル]アミノ]−3−ニトロフェニル]スルホニルベンズアミド(ABT−737とも呼ばれる)、
又は、
− 4−[4−[[2−(4−クロロフェニル)−5,5−ジメチルシクロヘキセン−1−イル]メチル]ピペラジン−1−イル]−N−[4−[[(2R)−4−モルホリン−4−イル−1−フェニルスルファニルブタン−2−イル]アミノ]−3−(トリフルオロメチルスルホニル)フェニル]スルホニルベンズアミド(ABT−263とも呼ばれる)
と一緒に投与される。
In a particular embodiment, the compound of formula (I) is preferably a Bcl-x L inhibitor, in particular a BH3 analogue inhibitor, for example
2-amino-6-bromo-α-cyano-3- (ethoxycarbonyl) -4H-1-benzopyran-4-acetic acid ethyl ester (also called HA14-1),
-4- [4-[[2- (4-Chlorophenyl) phenyl] methyl] piperazin-1-yl] -N- [4-[[(2R) -4- (dimethylamino) -1-phenylsulfanylbutane- 2-yl] amino] -3-nitrophenyl] sulfonylbenzamide (also called ABT-737),
Or
4- [4-[[2- (4-chlorophenyl) -5,5-dimethylcyclohexen-1-yl] methyl] piperazin-1-yl] -N- [4-[[(2R) -4-morpholine -4-yl-1-phenylsulfanylbutan-2-yl] amino] -3- (trifluoromethylsulfonyl) phenyl] sulfonylbenzamide (also called ABT-263)
Is administered together.
別の態様では、Mcl−1タンパク質を介したアポトーシスを誘導するために使用される式(I)の化合物が含まれる。 Another embodiment includes a compound of formula (I) used to induce apoptosis through the Mcl-1 protein.
患者は、臨床的に有益な結果が続くのであればいつでも効果的に治療される。このことは、例えば、疾患の症状の完全な回復、疾患の症状の重症度の低下、又は疾患の進行を遅らせることを意味することができる。 Patients are effectively treated whenever clinically beneficial results persist. This can mean, for example, complete recovery of disease symptoms, reduced severity of disease symptoms, or slowing disease progression.
本明細書で提供される有効量の任意の組成物は、治療を必要とする個体に投与可能である。本明細書で使用する場合、用語「有効」とは、患者に顕著な毒性を誘発せずに所望の反応を誘発する任意の量を意味する。このような量は、既知量の特定の組成物を投与した後の患者の反応を評価することによって決定することができる。 An effective amount of any composition provided herein can be administered to an individual in need of treatment. As used herein, the term “effective” means any amount that elicits the desired response without inducing significant toxicity in the patient. Such an amount can be determined by evaluating the patient's response after administration of a known amount of a particular composition.
Mcl−1の調節に反応する癌の治療方法
本発明はまた、癌を治療するために組成物を投与する方法、癌細胞を殺す方法、及び細胞中のMcl−1レベルを調節する方法にも関する。本明細書に記載されている治療方法は、その他の細胞毒性療法(例えば、化学療法、ホルモン療法、放射線療法、及び抗体に基づく療法)と共に実施することができる。
The present invention also relates to a method of administering a composition to treat cancer, a method of killing cancer cells, and a method of modulating Mcl-1 levels in cells. Related. The treatment methods described herein can be performed with other cytotoxic therapies (eg, chemotherapy, hormone therapy, radiation therapy, and antibody-based therapy).
好ましい実施形態では、本発明の化合物及び組成物は、Mcl−1発現癌を患う患者において転移又は更なる播種を防止又は減少させるのに有用である。より具体的には、本発明の化合物及び組成物は、このような患者の生存期間の増加、このような患者の無進行生存の増加、反応持続期間の増加に有用であり、生存期間、無進行生存、反応率又は反応持続期間を測定したときに統計学的に有意且つ臨床的に意味のある治療患者の改善をもたらす。好ましい実施形態では、医薬品は患者群の反応率の増加に有用である。 In preferred embodiments, the compounds and compositions of the invention are useful for preventing or reducing metastasis or further dissemination in patients suffering from Mcl-1-expressing cancer. More specifically, the compounds and compositions of the invention are useful for increasing the survival of such patients, increasing the progression free survival of such patients, increasing the duration of response, It provides statistically significant and clinically meaningful improvements in treated patients when measuring progression survival, response rate, or response duration. In a preferred embodiment, the medicament is useful for increasing the response rate of a group of patients.
本発明の1つ又は複数の実施形態の詳細を、添付図面及び以下の説明に示す。本発明の他の特徴、目的、及び利点は、説明及び図面、並びに特許請求の範囲から明らかになるであろう。 The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
定義
本明細書に含まれる以下の用語及び表現は、次のように定義される。
Definitions The following terms and expressions contained herein are defined as follows:
本明細書で使用する場合、用語「アルキル」とは、1〜8個の炭素原子を有する直鎖又は分岐鎖アルキル基、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、イソアミル、ネオペンチル、1−エチルプロピル、3−メチルペンチル、2,2−ジメチルブチル、2,3−ジメチルブチル、ヘキシル、オクチル等を意味する。アルコキシ及びアルコキシカルボニル等のアルキル含有基のアルキル部分は上記定義のアルキルと同じ意味を有する。好ましい低級アルキル基は、1〜4個の炭素を含む上記定義のアルキル基である。「C1〜C6アルキル」等の表記は、1〜6個の炭素原子を含むアルキル基を意味する。 As used herein, the term “alkyl” refers to a straight or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, It means tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, hexyl, octyl and the like. The alkyl part of an alkyl-containing group such as alkoxy and alkoxycarbonyl has the same meaning as alkyl as defined above. Preferred lower alkyl groups are alkyl groups as defined above containing 1 to 4 carbons. A notation such as “C 1 -C 6 alkyl” means an alkyl group containing 1 to 6 carbon atoms.
本明細書で使用する場合、用語「アルケニル」とは、少なくとも1つの炭素−炭素二重結合を有する2〜6個の炭素原子の直鎖又は分岐炭化水素鎖を意味する。「C2〜C6アルケニル」という表記は、2〜6個の炭素原子を含むアルケニル基を意味する。アルケニル基の例としては、エテニル、プロペニル、イソプロペニル、2,4−ペンタジエニルが挙げられる。「C2〜C4アルケニル」が特に好ましい。 As used herein, the term “alkenyl” means a straight or branched hydrocarbon chain of 2 to 6 carbon atoms having at least one carbon-carbon double bond. The notation “C 2 -C 6 alkenyl” means an alkenyl group containing 2 to 6 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, and 2,4-pentadienyl. “C 2 -C 4 alkenyl” is particularly preferred.
本明細書で使用する場合、用語「アルコキシ」とは、アルキル基が本明細書に記載された通りのものであるアルキル−O−基を意味する。例示的なアルコキシ基としては、メトキシ、エトキシ、n−プロポキシ、i−プロポキシ、及びnーブトキシが挙げられる。 As used herein, the term “alkoxy” means an alkyl-O— group in which the alkyl group is as described herein. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, and n-butoxy.
本明細書で使用する場合、用語「アリール」とは、6〜10個の環炭素原子を有する置換又は非置換の単環式又は二環式芳香族環系を意味する。例としては、フェニル及びナフチルが挙げられる。 As used herein, the term “aryl” means a substituted or unsubstituted monocyclic or bicyclic aromatic ring system having 6 to 10 ring carbon atoms. Examples include phenyl and naphthyl.
本明細書で使用する場合、用語「アリールアルキル」とは、アリール基で置換されたアルキル基を意味する。アリールアルキル基の例としては、ベンジル、ブロモベンジル、フェネチル、ベンズヒドリル、ジフェニルメチル、トリフェニルメチル、ジフェニルエチル、ナフチルメチルが挙げられるが、これらに限定されない。 As used herein, the term “arylalkyl” refers to an alkyl group substituted with an aryl group. Examples of arylalkyl groups include, but are not limited to, benzyl, bromobenzyl, phenethyl, benzhydryl, diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl.
本明細書で使用する場合、用語「アルキルアルケニル」とは、アリール基で置換されたアルケニル基を意味する。アリールアルケニルの例としては、スチリルが挙げられるが、これに限定されない。 As used herein, the term “alkylalkenyl” refers to an alkenyl group substituted with an aryl group. Examples of arylalkenyl include, but are not limited to, styryl.
本明細書で使用する場合、用語「アリールカルボニル」とは、アリール基が本明細書に記載された通りのものであるアリール−C(=O)−基を意味する。 As used herein, the term “arylcarbonyl” means an aryl-C (═O) — group in which the aryl group is as described herein.
本明細書で使用する場合、用語「アリールアルキルカルボニル」とは、アリールアルキル基が本明細書に記載された通りのものであるアリールアルキル−C(=O)−基を意味する。 As used herein, the term “arylalkylcarbonyl” means an arylalkyl-C (═O) — group in which the arylalkyl group is as described herein.
本明細書で使用する場合、用語「ヘテロアリール」とは、1又は複数の環炭素原子が−O−、−N−、又は−S−等の少なくとも1つのヘテロ原子で置換されている5〜10個、好ましくは5〜7個の環炭素原子を含む芳香族基を意味する。ヘテロアリール基の例としては、ピロリル、フラニル、チエニル、ピラゾリル、イミダゾリル、チアゾリル、イソチアゾリル、イソキサゾリル、オキサゾリル、オキサチオリル、オキサジアゾリル、トリアゾリル、オキサトリアゾリル、フラザニル、テトラゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、トリアジニル、インドリル、イソインドリル、インダゾリル、ベンゾフラニル、イソベンゾフラニル、プリニル、キナゾリニル、キノリル、イソキノリル、ベンゾイミダゾリル、ベンゾチアゾリル、ベンゾチオフェニル、チアナフテニル、ベンズオキサゾリル、ベンズイソキサゾリル、シンノリニル、フタラジニル、ナフチリジニル、及びキノキサリニルが挙げられる。「ヘテロアリール」の定義内には、例えば、芳香環がヘテロシクロアルキル環に縮合された環系を含む縮合環系が含まれる。このような縮合環系の例としては、例えば、フタルアミド、無水フタル酸、インドリン、イソインドリン、テトラヒドロイソキノリン、クロマン、イソクロマン、クロメン、及びイソクロメンが挙げられる。 As used herein, the term “heteroaryl” refers to a group in which one or more ring carbon atoms are replaced with at least one heteroatom such as —O—, —N—, or —S—. An aromatic group containing 10 and preferably 5 to 7 ring carbon atoms is meant. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxathiolyl, oxadiazolyl, triazolyl, oxatriazolyl, furazanyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl , Indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, purinyl, quinazolinyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl, benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, phthalazinyl, naphthyridinyl, and Quinoxalinyl is mentioned. Included within the definition of “heteroaryl” are fused ring systems, including, for example, ring systems in which an aromatic ring is fused to a heterocycloalkyl ring. Examples of such fused ring systems include, for example, phthalamide, phthalic anhydride, indoline, isoindoline, tetrahydroisoquinoline, chroman, isochroman, chromene, and isochromene.
本明細書で使用する場合、用語「対象」とは、本明細書に記載される1又は複数の疾患及び状態に苦しむ、又は苦しんでいる可能性がある哺乳動物、好ましくはヒト又はヒトの子供等の温血動物を意味する。 As used herein, the term “subject” refers to a mammal, preferably a human or a human child, that suffers from or may be suffering from one or more of the diseases and conditions described herein. Means warm-blooded animals.
本明細書で使用する場合、「治療有効量」とは、特定の障害の症状を予防又は治療するのに有効な本発明の化合物の量を意味する。このような障害としては、本明細書に記載される受容体の異常な活性と関連する病理学的障害及び神経障害が挙げられるが、これらに限定されない。治療又は予防は、受容体と本発明の化合物とを接触させることによってその活性を阻害、誘発、又は増強することを含む。 As used herein, “therapeutically effective amount” means an amount of a compound of the invention effective to prevent or treat the symptoms of a particular disorder. Such disorders include, but are not limited to, pathological disorders and neurological disorders associated with abnormal activity of the receptors described herein. Treatment or prevention includes inhibiting, inducing or enhancing its activity by contacting the receptor with a compound of the invention.
本明細書で使用する場合、用語「薬学的に許容される」とは、健全な医学的判断の範囲内における、妥当な利益/リスク比と釣り合う、過度の毒性、刺激、アレルギー反応、又は他の問題となる合併症を伴うことなくヒト及び動物の組織と接触するのに適した化合物、物質、組成物、及び/又は投薬形態を意味する。 As used herein, the term “pharmaceutically acceptable” refers to an excessive toxicity, irritation, allergic reaction, or other that is commensurate with a reasonable benefit / risk ratio within the scope of sound medical judgment. Means a compound, substance, composition and / or dosage form suitable for contact with human and animal tissues without the complications of
本発明の記述に用いられるその他用語の意味は、当該技術分野において周知である。 The meanings of other terms used in the description of the present invention are well known in the art.
別の態様では、本発明は、上述の化合物の薬学的に許容される塩に関する。本明細書で使用する場合、「薬学的に許容される塩」は、本発明の化合物と非毒性の酸又は塩基付加塩の組み合わせから誘導されたかかる化合物の塩を含む。 In another aspect, the invention relates to pharmaceutically acceptable salts of the aforementioned compounds. As used herein, “pharmaceutically acceptable salts” include salts of such compounds derived from the combination of a compound of the present invention and a non-toxic acid or base addition salt.
酸付加塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、及びリン酸等の無機酸並びに酢酸、クエン酸、プロピオン酸、酒石酸、グルタミン酸、サリチル酸、シュウ酸、メタンスルホン酸、p−トルエンスルホン酸、コハク酸、及び安息香酸等の有機酸、並びに無機酸及び有機酸が挙げられる。 Acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acetic acid, citric acid, propionic acid, tartaric acid, glutamic acid, salicylic acid, oxalic acid, methanesulfonic acid , P-toluenesulfonic acid, succinic acid, benzoic acid and other organic acids, and inorganic acids and organic acids.
塩基付加塩としては、アンモニウム並びにアルカリ金属及びアルカリ土類金属の水酸化物、炭酸塩、及び重炭酸塩等の無機塩基から誘導される塩、並びに脂肪族アミン及び芳香族アミン、脂肪族ジアミン、ヒドロキシアルカミン等の塩基性有機アミンから誘導される塩が挙げられる。従って、本発明の塩の調製において有用なこのような塩基としては、水酸化アンモニウム、炭酸カリウム、重炭酸ナトリウム、水酸化カルシウム、メチルアミン、ジエチルアミン、エチレンジアミン、シクロヘキシルアミン、エタノールアミン等が挙げられる。 Base addition salts include salts derived from ammonium and inorganic bases such as alkali and alkaline earth metal hydroxides, carbonates, and bicarbonates, and aliphatic and aromatic amines, aliphatic diamines, And salts derived from basic organic amines such as hydroxyalkamines. Accordingly, such bases useful in the preparation of the salts of the present invention include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.
薬学的に許容される塩に加えて、その他塩が本発明に包含される。それらは、化合物の精製、その他塩の調製、又は化合物若しくは中間体の同定及び特性決定における中間体としての役割を果たしうる。 In addition to pharmaceutically acceptable salts, other salts are encompassed by the present invention. They may serve as intermediates in the purification of compounds, the preparation of other salts, or the identification and characterization of compounds or intermediates.
I.式(I)の化合物の合成
材料及び方法を以下に述べる。
I. Synthesis of compounds of formula (I) Materials and methods are described below.
材料
市販試薬を更なる精製を行わずに受け取ったときの状態で使用した。融点をコフラー(Kofler)加熱ベンチで決定した。IRスペクトルをPerkin Elmer社製BX FT−IR分光光度計で記録した。バンド位置は毎センチメートル(cm−1)で与えられる。1H NMR(400MHz)及び13C NMR(100MHz)スペクトルをJEOL社製Lambda400スペクトロメータで記録した。ケミカルシフトは内部標準であるテトラメチルシランからのダウンフィールドで百万分率により表し、結合定数はヘルツで表される。ケミカルシフトは溶媒共鳴に対する百万分率(ppm)で報告される。固定相としてフラッシュシリカゲル60、Merck社製(0.063〜0.200mm)を使用してカラムクロマトグラフィーを行った。各精製で指定される溶出溶媒は、シリカゲル60F−264(Merck社製)の0.2mmプレコートプレートで行われた薄層クロマトグラフィー(TLC)により決定され、紫外線ランプを使用してスポットを可視化した。新たな化合物の元素分析を行い、C、H、及びNのデータはすべての最終化合物の理論値の±0.4以内であった。
Materials Commercial reagents were used as received without further purification. The melting point was determined on a Kofler heating bench. IR spectra were recorded on a Perkin Elmer BX FT-IR spectrophotometer. Band positions are given in centimeters (cm −1 ). 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were recorded with a Lambda 400 spectrometer manufactured by JEOL. The chemical shift is expressed in parts per million in the downfield from the internal standard tetramethylsilane, and the coupling constant is expressed in hertz. Chemical shifts are reported in parts per million (ppm) relative to solvent resonance. Column chromatography was performed using Flash Silica Gel 60 as a stationary phase, Merck (0.063-0.200 mm). The elution solvent specified in each purification was determined by thin layer chromatography (TLC) performed on a 0.2 mm pre-coated plate of silica gel 60F-264 (Merck), and the spots were visualized using an ultraviolet lamp. . Elemental analysis of the new compound was performed and C, H, and N data were within ± 0.4 of the theoretical values for all final compounds.
方法
本発明の(ヘテロ)芳香族オリゴ系は、以下のスキーム1及び実施例1に記述される5−ブロモ−2−ヒドロキシピリジン1、トランス−フェニルビニルボロン酸4、及び6−ブロモ−5−メチルピリジン−3−イルボロン酸7からMR29072を得るのに使用される手順と同じ手順に従って合成された。
Method The (hetero) aromatic oligo system of the present invention comprises 5-bromo-2-hydroxypyridine 1, trans-phenylvinylboronic acid 4, and 6-bromo-5- 5- described in Scheme 1 and Example 1 below. Synthesized according to the same procedure used to obtain MR29072 from methylpyridin-3-ylboronic acid 7.
実施例1:5,6’−ジ(ピリジン−3−イル)−5’−メチル−3−((E)−スチリル)−2,3’−ビピリジン(MR29072) Example 1: 5,6'-di (pyridin-3-yl) -5'-methyl-3-((E) -styryl) -2,3'-bipyridine (MR29072)
5−ブロモ−2−ヒドロキシピリジン1(5g、29mmol)に固体N−ヨードスクシンイミド(7.1g、32mmol)/アセトニトリル(120mL)を添加した。溶液を還流状態にて4時間撹拌し、その後TLCを行った。溶液を室温まで冷却し、ろ過し、メタノールで洗浄した。5−ブロモ−2−ヒドロキシ−3−ヨードピリジン2はピンク色の固体として得られた(収率83%)。 To 5-bromo-2-hydroxypyridine 1 (5 g, 29 mmol) was added solid N-iodosuccinimide (7.1 g, 32 mmol) / acetonitrile (120 mL). The solution was stirred at reflux for 4 hours, followed by TLC. The solution was cooled to room temperature, filtered and washed with methanol. 5-Bromo-2-hydroxy-3-iodopyridine 2 was obtained as a pink solid (83% yield).
2(9g、30mmol)をフェニルホスホン酸ジクロリド90%(100mL、0.3mol)中に溶解させた。混合物を4時間撹拌及び加熱し(160℃)、その後TLCを行った。室温にて、これを水で満たされた1Lバイアルに滴下し、0℃で冷却した。NH4OH溶液を添加することにより、溶液を中和した。混合物を酢酸エチル中で抽出した。生成物は、白色固体の5−ブロモ−2−クロロ−3−ヨードピリジン3として得られた(収率82%)。 2 (9 g, 30 mmol) was dissolved in 90% (100 mL, 0.3 mol) of phenylphosphonic dichloride. The mixture was stirred and heated for 4 hours (160 ° C.) followed by TLC. At room temperature, it was added dropwise to a 1 L vial filled with water and cooled at 0 ° C. The solution was neutralized by adding NH 4 OH solution. The mixture was extracted in ethyl acetate. The product was obtained as white solid 5-bromo-2-chloro-3-iodopyridine 3 (82% yield).
3(5g、15.7mmol)を含有する窒素環境下の反応槽(100mL)に、トランス−フェニルビニルボロン酸4(2.7g、18mmol)、テトラキストリフェニルホスフィン(907mg、0.8mmol)、炭酸ナトリウム(4.2g、39mmol)/1,4−ジオキサン(100mL)を添加した。出発物質を消費するまで混合物を還流状態にて24時間撹拌し、その後TLCを行った。生成物は室温まで冷却し、これをセライトろ過した。MgSO4を用いて溶液を乾燥させ、ろ過し、蒸発させた。残渣をクロマトグラフィー(c−ヘキサン:酢酸エチル=99:1、その後98:2)によって精製し、5ーブロモ−2−クロロ−3−((E)−スチリル)−ピリジン5を得た(収率93%。)。 3 (5 g, 15.7 mmol) in a reaction vessel (100 mL) under a nitrogen environment, trans-phenylvinylboronic acid 4 (2.7 g, 18 mmol), tetrakistriphenylphosphine (907 mg, 0.8 mmol), carbonic acid Sodium (4.2 g, 39 mmol) / 1,4-dioxane (100 mL) was added. The mixture was stirred at reflux for 24 hours until the starting material was consumed, followed by TLC. The product was cooled to room temperature and filtered through celite. MgSO 4 dried solution using, filtered and evaporated. The residue was purified by chromatography (c-hexane: ethyl acetate = 99: 1, then 98: 2) to give 5-bromo-2-chloro-3-((E) -styryl) -pyridine 5 (yield) 93%.)
5(200mg、0.7mmol)にヨウ化ナトリウム(1g、6.8mmol)、塩化アセチル(0.07mL、1mmol)、及びアセトニトリル(10mL)を添加した。混合物をマイクロ波照射しながら1時間100℃で撹拌した。室温にて、NaHCO3溶液により混合物を中和した。抽出及び亜硫酸水素ナトリウム固体/水を用いた洗浄の後、MgSO4を用いて有機層を乾燥させ、ろ過し、蒸発させた。生成物をクロマトグラフィー(c−ヘキサン:酢酸エチル=98:2、その後95:5)によって精製し、5ーブロモ−2−ヨード−3−((E)−スチリル)−ピリジン6を得た(収率84%)。 To 5 (200 mg, 0.7 mmol) was added sodium iodide (1 g, 6.8 mmol), acetyl chloride (0.07 mL, 1 mmol), and acetonitrile (10 mL). The mixture was stirred at 100 ° C. for 1 hour with microwave irradiation. At room temperature, the mixture was neutralized with NaHCO 3 solution. After extraction and washing with sodium hydrogen sulfite solid / water, the organic layer was dried with MgSO 4 , filtered and evaporated. The product was purified by chromatography (c-hexane: ethyl acetate = 98: 2, then 95: 5) to give 5-bromo-2-iodo-3-((E) -styryl) -pyridine 6 (yield). 84%).
6(1.4g、3.6mmol)を含有する窒素雰囲気下の反応槽(100mL)に、6−ブロモ−5−メチルピリジン−3−イルボロン酸7(978mg、4.5mmol)、テトラキストリフェニルホスフィン(210mg、0.18mmol)、リン酸カリウム(2.1g、9mmol)/1,2−ジメトキシエタン(30mL)を添加した。出発物質を消費するまで混合物を還流状態にて20時間撹拌し、その後TLCを行った。室温にて、溶液を酢酸エチルで抽出した。MgSO4を用いて有機層を乾燥させ、ろ過し、蒸発させた。残渣をクロマトグラフィー(c−ヘキサン:酢酸エチル=95:5、その後9:1及び8:2)によって精製し、5,6’ージブロモ−5’−メチル−3−((E)−スチリル)−2,3’−ビピリジン8を得た(収率86%)。 6 (1.4 g, 3.6 mmol) in a reaction vessel (100 mL) under a nitrogen atmosphere, 6-bromo-5-methylpyridin-3-ylboronic acid 7 (978 mg, 4.5 mmol), tetrakistriphenylphosphine (210 mg, 0.18 mmol), potassium phosphate (2.1 g, 9 mmol) / 1,2-dimethoxyethane (30 mL) was added. The mixture was stirred at reflux for 20 hours until the starting material was consumed, followed by TLC. At room temperature, the solution was extracted with ethyl acetate. The organic layer was dried using MgSO 4 , filtered and evaporated. The residue is purified by chromatography (c-hexane: ethyl acetate = 95: 5, then 9: 1 and 8: 2) and 5,6′-dibromo-5′-methyl-3-((E) -styryl)- 2,3′-bipyridine 8 was obtained (yield 86%).
8(320mg、0.7mmol)を含有する窒素雰囲気下の反応槽(100mL)に、ピリジン−3−イルボロン酸9(156mg、1.7mmol)、テトラキストリフェニルホスフィン(78mg、0.07mmol)、炭酸ナトリウム(355mg、3.35mmol)/1,4−ジオキサン(20mL)を添加した。出発物質を消費するまで混合物を還流状態にて24時間撹拌し、その後TLCを行った。室温にて、懸濁液をセライトろ過し、溶液を酢酸エチルで抽出した。MgSO4を用いて有機層を乾燥させ、ろ過し、蒸発させた。生成物をクロマトグラフィー(c−ヘキサン:酢酸エチル=8:2、その後7:3及び50:50)によって精製し、白色固体(Mp158℃)の5,6’ージ(ピリジン−3−イル)−5’−メチル−3−((E)−スチリル)−2,3’−ビピリジンMR29072を得た(収率86%)。IR(KBr):2957,1727,1575,1274,1125,1014,967,801,770,688cm−1.1H NMR(400MHz,CDCl3):δ8.98(d,4J=1.9Hz,1H),8.91(d,4J=1.9Hz,1H),8.87(m,2H),8.72(dd,3J=4.9Hz,4J=1.9Hz,2H),8.68(dd,3J=4.9Hz,4J=1.9Hz,1H),8.24(d,4J=1.9Hz,1H),8.00(m,3H),7.48(d,3J=7.8Hz,3H),7.44(dd,3J=7.8Hz,4J=1.9Hz,1H),7.36(d,3J=7.8Hz,1H),7.31(d,3J=7.8Hz,1H),7.28(d,3J=16.6Hz,1H),7.23(d,3J=16.6Hz,1H),2.51(s,3H).13C NMR(100MHz,CDCl3):δ155.3,153.4,149.9,149.6,149.2,148.2,148.0,146.9,139.8,136.5,136.3,135.8,134.4,134.1,133.1,133.0,132.9,132.6,132.0,131.1,128.8(2C),128.5,126.8(2C),124.6,123.8,123.2,20.0.LCMS(EI):m/z(%)=[M+H]+ theoretical:427.53,experimental:427.32.Anal.Calcd for C29H22N4:C,81.67;H,5.20;N,13.14.Found:C,81.65;H,5.25;N,13.23. Into a reaction vessel (100 mL) containing 8 (320 mg, 0.7 mmol) in a nitrogen atmosphere, pyridin-3-ylboronic acid 9 (156 mg, 1.7 mmol), tetrakistriphenylphosphine (78 mg, 0.07 mmol), carbonic acid Sodium (355 mg, 3.35 mmol) / 1,4-dioxane (20 mL) was added. The mixture was stirred at reflux for 24 hours until the starting material was consumed, followed by TLC. The suspension was filtered through Celite at room temperature, and the solution was extracted with ethyl acetate. The organic layer was dried using MgSO 4 , filtered and evaporated. The product was purified by chromatography (c-hexane: ethyl acetate = 8: 2, then 7: 3 and 50:50) and 5,6′-di (pyridin-3-yl) as a white solid (Mp158 ° C.) -5'-methyl-3-((E) -styryl) -2,3'-bipyridine MR29072 was obtained (yield 86%). IR (KBr): 2957, 1727, 1575, 1274, 1125, 1014, 967, 801, 770, 688 cm −1 . 1 H NMR (400 MHz, CDCl 3 ): δ 8.98 (d, 4 J = 1.9 Hz, 1H), 8.91 (d, 4 J = 1.9 Hz, 1H), 8.87 (m, 2H) , 8.72 (dd, 3 J = 4.9 Hz, 4 J = 1.9 Hz, 2H), 8.68 (dd, 3 J = 4.9 Hz, 4 J = 1.9 Hz, 1H), 8.24. (D, 4 J = 1.9 Hz, 1H), 8.00 (m, 3H), 7.48 (d, 3 J = 7.8 Hz, 3H), 7.44 (dd, 3 J = 7.8 Hz , 4 J = 1.9 Hz, 1H), 7.36 (d, 3 J = 7.8 Hz, 1H), 7.31 (d, 3 J = 7.8 Hz, 1H), 7.28 (d, 3 J = 16.6 Hz, 1H), 7.23 (d, 3 J = 16.6 Hz, 1H), 2.51 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ 155.3, 153.4, 149.9, 149.6, 149.2, 148.2, 148.0, 146.9, 139.8, 136.5 136.3, 135.8, 134.4, 134.1, 133.1, 133.0, 132.9, 132.6, 132.0, 131.1, 128.8 (2C), 128.5 , 126.8 (2C), 124.6, 123.8, 123.2, 20.0. LCMS (EI): m / z (%) = [M + H] + theoretical: 427.53, experimental: 427.32. Anal. Calcd for C 29 H 22 N 4 : C, 81.67; H, 5.20; N, 13.14. Found: C, 81.65; H, 5.25; N, 13.23.
この最初の手順は、3−メチル−5−(3−(E)−スチリル−5−(チオフェン−3−イル)ピリジン−2−イル)−2−(チオフェン−3−イル)ピリジン(MR31322)、3−メチル−2−(3−メチルチオフェン−2−イル)−5−(5−(3−メチルチオフェン−2−イル)−3−(E)−スチリルピリジン−2−イル)ピリジン(MR31336)、3−メチル−5−(3−(E)−スチリル−5−(チオフェン−2−イル)ピリジン−2−イル)−2−(チオフェン−2−イル)ピリジン(MR31321)、2−(5−メチル−6−(1H−ピラゾール−5−イル)ピリジン−3−イル)−5−(1H−ピラゾール−5−イル)−3−スチリルピリジン(MR31363)、5−(2−クロロ−1−メチル−1H−イミダゾール−5−イル)−2−(6−(2−クロロ−1−メチル−1H−イミダゾール−5−イル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR31351)、3−メチル−2−(4−シアノフェニル)−5−(5−(4−シアノフェニル)−3−スチリルピリジン−2−イル)ピリジンMR30854、5−(3,4,5−トリメトキシフェニル)−2−(6−(3,4,5−トリメトキシフェニル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR30847)、2−(3,4−ジメトキシフェニル)−5−(5−(3,4−ジメトキシフェニル)−3−スチリルピリジン−2−イル)−3−メチルピリジン(MR30846)、4−(3−メチル−5−(5−(ピリジン−4−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)ピリジン(MR31350)、3−メチル−2−フェニル−5−(5−フェニル−3−スチリルピリジン−2−イル)ピリジン(MR30814)、5−(3−メチル−5−(5−(ピリミジン−5−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)ピリミジン(MR31361)の化合物に適用される。 This initial procedure was followed by 3-methyl-5- (3- (E) -styryl-5- (thiophen-3-yl) pyridin-2-yl) -2- (thiophen-3-yl) pyridine (MR31322). 3-methyl-2- (3-methylthiophen-2-yl) -5- (5- (3-methylthiophen-2-yl) -3- (E) -styrylpyridin-2-yl) pyridine (MR31336) ), 3-methyl-5- (3- (E) -styryl-5- (thiophen-2-yl) pyridin-2-yl) -2- (thiophen-2-yl) pyridine (MR31321), 2- ( 5-methyl-6-(1 H- pyrazol-5-yl) pyridin-3-yl) -5- (1H-pyrazol-5-yl) -3- styrylpyridine (MR31363), 5- (2- chloro - 1-methyl-1H-i Dazol-5-yl) -2- (6- (2-chloro-1-methyl-1H-imidazol-5-yl) -5-methylpyridin-3-yl) -3-styrylpyridine (MR31351), 3- Methyl-2- (4-cyanophenyl) -5- (5- (4-cyanophenyl) -3-styrylpyridin-2-yl) pyridine MR30854, 5- (3,4,5-trimethoxyphenyl) -2 -(6- (3,4,5-trimethoxyphenyl) -5-methylpyridin-3-yl) -3-styrylpyridine (MR30847), 2- (3,4-dimethoxyphenyl) -5- (5- (3,4-Dimethoxyphenyl) -3-styrylpyridin-2-yl) -3-methylpyridine (MR30846), 4- (3-methyl-5- (5- (pyridin-4-yl) -3-styryl Rupyridin-2-yl) pyridin-2-yl) pyridine (MR31350), 3-methyl-2-phenyl-5- (5-phenyl-3-styrylpyridin-2-yl) pyridine (MR30814), 5- (3 -Applies to the compound of methyl-5- (5- (pyrimidin-5-yl) -3-styrylpyridin-2-yl) pyridin-2-yl) pyrimidine (MR31361).
本出願人は、窒素雰囲気下でチオフェン−3−ボロン酸、3−メチル−チオフェン−2−ボロン酸、チオフェン−2−ボロン酸、1−(テトラヒドロ−2H−ピラン−2−イル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキソボロラン−2−イル)−1H−ピラゾール、2−クロロ−1−メチル−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−イミダゾール、4−シアノフェニルボロン酸、3,4,5−トリメトキシフェニルボロン酸、3,4−ジメトキシフェニルボロン酸、4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ピリジン、ベンゼンボロン酸、ピリミジン−5−イル−ボロン酸、テトラキストリフェニルホスフィン、炭酸ナトリウム/1,4−ジオキサン(20mL)を有する反応槽(100mL)に導入された5,6’−ジブロモ−5’−メチル−3−((E)−スチリル)−2,3’−ビピリジンから、MR31322、MR31336、MR31321、MR31363、MR31351、MR30854、MR30847、MR30846、MR31350、MR30814、MR31361をそれぞれ得た。 Applicants have found that thiophene-3-boronic acid, 3-methyl-thiophene-2-boronic acid, thiophene-2-boronic acid, 1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl) -1H-pyrazole, 2-chloro-1-methyl-5- (4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl) -1H-imidazole, 4-cyanophenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, 4- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, benzeneboronic acid, pyrimidin-5-yl-boronic acid, tetrakistriphenylphosphine, sodium carbonate From 5,6′-dibromo-5′-methyl-3-((E) -styryl) -2,3′-bipyridine introduced into a reaction vessel (100 mL) with dimethyl-1,4-dioxane (20 mL) , MR31322, MR31336, MR31321, MR31363, MR31351, MR30854, MR30847, MR30846, MR31350, MR30814 and MR31361 were obtained.
実施例2:3−メチル−5−(3−(E)−スチリル−5−(チオフェン−2−イル)ピリジン−2−イル)−2−(チオフェン−2−イル)ピリジン(MR31321) Example 2: 3-Methyl-5- (3- (E) -styryl-5- (thiophen-2-yl) pyridin-2-yl) -2- (thiophen-2-yl) pyridine (MR31321)
1H−NMR(CDCl3)δ8.90(d,1H,H6’,J=1.96Hz),8.73(d,1H,H6,J=1.96Hz),8.18(d,1H,H4’,J=1.96Hz),7.95(d,1H,H4,J=1.96Hz),7.58(d,1H,H3’’’,J=3.87Hz),7.49−7.46(m,4H,2H ortho Ph,H5’’及びH5’’’),7.43(d,1H,H3’,J=3.87Hz),7.38−7.34(dd,2H meta Ph,J=7Hz),7.30(m,1H para Ph,J=7Hz),7.20(s,2H,CH=CH),7.19−7.17(m,2H,H4’’及びH4’’’),2.68(3H,CH3).
MS(EI):437[M+]*.
1 H-NMR (CDCl 3 ) δ 8.90 (d, 1H, H6 ′, J = 1.96 Hz), 8.73 (d, 1H, H6, J = 1.96 Hz), 8.18 (d, 1H , H4 ′, J = 1.96 Hz), 7.95 (d, 1H, H4, J = 1.96 Hz), 7.58 (d, 1H, H3 ′ ″, J = 3.87 Hz), 7. 49-7.46 (m, 4H, 2H ortho Ph, H5 ″ and H5 ′ ″), 7.43 (d, 1H, H3 ′, J = 3.87 Hz), 7.38-7.34 ( dd, 2H meta Ph, J = 7 Hz), 7.30 (m, 1H para Ph, J = 7 Hz), 7.20 (s, 2H, CH = CH), 7.19-7.17 (m, 2H) , H4 ″ and H4 ″ ′), 2.68 (3H, CH 3 ).
MS (EI): 437 [M +] * .
実施例3:3−メチル−5−(3−(E)−スチリル−5−(チオフェン−3−イル)ピリジン−2−イル)−2−(チオフェン−3−イル)ピリジン(MR31322) Example 3: 3-Methyl-5- (3- (E) -styryl-5- (thiophen-3-yl) pyridin-2-yl) -2- (thiophen-3-yl) pyridine (MR31322)
1H−NMR(CDCl3)δ8.89(d,1H,H6,J=1.92Hz),8.77(d,1H,H6’,J=1.92Hz),8.21(d,1H,H4,J=1.92Hz),7.96(1H,H4’,J=1.92Hz),7.68−7.66(dd,2H,H5’’及びH5’’’,J=2.92Hz,J=7.4Hz),7.57(d,1H,H para Ph,J=7Hz),7.51(d,2H,H2’’及びH5’’’,J=2.92Hz),7.47(d,2H ortho Ph,J=7Hz),7.43− 7.41(dd,2H,H4’’及びH4’’’,J=2.92Hz),7.38−7.34(dd,2H meta Ph,J=7Hz),7.26−7.21(m,2H,CH=CH),2.68(s,3H,CH3).
MS(EI):437[M+]*.
1 H-NMR (CDCl 3 ) δ 8.89 (d, 1H, H6, J = 1.92 Hz), 8.77 (d, 1H, H6 ′, J = 1.92 Hz), 8.21 (d, 1H , H4, J = 1.92 Hz), 7.96 (1H, H4 ′, J = 1.92 Hz), 7.68-7.66 (dd, 2H, H5 ″ and H5 ′ ″, J = 2). .92 Hz, J = 7.4 Hz), 7.57 (d, 1H, H para Ph, J = 7 Hz), 7.51 (d, 2H, H2 ″ and H5 ′ ″, J = 2.92 Hz) 7.47 (d, 2H ortho Ph, J = 7 Hz), 7.43-7.41 (dd, 2H, H4 ″ and H4 ′ ″, J = 2.92 Hz), 7.38-7. 34 (dd, 2H meta Ph, J = 7Hz), 7.26-7.21 (m, 2H, CH = CH), 2.68 (s, 3H, CH 3).
MS (EI): 437 [M +] * .
実施例4:3−メチル−2−(3−メチルチオフェン−2−イル)−5−(5−(3−メチルチオフェン−2−イル)−3−(E)−スチリルピリジン−2−イル)ピリジン(MR31336) Example 4: 3-methyl-2- (3-methylthiophen-2-yl) -5- (5- (3-methylthiophen-2-yl) -3- (E) -styrylpyridin-2-yl) Pyridine (MR31336)
1H−NMR(CDCl3):8.68(d,1H,H6,J=1.92Hz),8.59(d,1H,H6’,J=1.92Hz),8.07(d,1H,H4,J=1.92Hz),7.95(d,1H,H4’,J=1.92Hz),7.52−7.28(m,7H),7.25−7.6.95(m,4H),2.41(s,3H,CH3),2.16(s,3H,CH3),2.03(s,3H,CH3).
MS(EI):466[M++H,100].
1 H-NMR (CDCl 3 ): 8.68 (d, 1H, H6, J = 1.92 Hz), 8.59 (d, 1H, H6 ′, J = 1.92 Hz), 8.07 (d, 1H, H4, J = 1.92 Hz), 7.95 (d, 1H, H4 ′, J = 1.92 Hz), 7.52-7.28 (m, 7H), 7.25-7.6. 95 (m, 4H), 2.41 (s, 3H, CH 3), 2.16 (s, 3H, CH 3), 2.03 (s, 3H, CH 3).
MS (EI): 466 [M ++ H, 100].
実施例5:2−(5−メチル−6−(1H−ピラゾール−5−イル)ピリジン−3−イル)−5−(1H−ピラゾール−5−イル)−3−スチリルピリジン(MR31363) Example 5: 2- (5-Methyl-6- (1H-pyrazol-5-yl) pyridin-3-yl) -5- (1H-pyrazol-5-yl) -3-styrylpyridine (MR31363)
1H−NMR(d6−DMSO):δ9.08(d,1H,J=1.7Hz),8.65(d,1H,J=1.7Hz),8.58(d,1H,J=1.7Hz),7.98(d,1H,J=1.6Hz),7.86(d,1H,J=1.5Hz),7.76(bs,1H),7.55(d,2H,J=7.8Hz),7.45(d,1H,CH=CH,J=16.4Hz),7.40−7.36(m,2H),7.31−7.27(m,1H),7.22(d,1H,CH=CH,J=16.4Hz,),7.02(d,1H,J=2.16),6.86(m,1H),6.53(bs,1H),2.65(s,3H,CH3).
MS(EI):405.60[M+]*.
1 H-NMR (d 6 -DMSO): δ 9.08 (d, 1H, J = 1.7 Hz), 8.65 (d, 1H, J = 1.7 Hz), 8.58 (d, 1H, J = 1.7 Hz), 7.98 (d, 1 H, J = 1.6 Hz), 7.86 (d, 1 H, J = 1.5 Hz), 7.76 (bs, 1 H), 7.55 (d , 2H, J = 7.8 Hz), 7.45 (d, 1H, CH = CH, J = 16.4 Hz), 7.40-7.36 (m, 2H), 7.31-7.27 ( m, 1H), 7.22 (d, 1H, CH = CH, J = 16.4 Hz,), 7.02 (d, 1H, J = 2.16), 6.86 (m, 1H), 6 .53 (bs, 1H), 2.65 (s, 3H, CH 3 ).
MS (EI): 405.60 [M <+ >] * .
実施例6:5−(2−クロロ−1−メチル−1H−イミダゾール−5−イル)−2−(6−(2−クロロ−1−メチル−1H−イミダゾール−5−イル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR31351) Example 6: 5- (2-Chloro-1-methyl-1H-imidazol-5-yl) -2- (6- (2-chloro-1-methyl-1H-imidazol-5-yl) -5-methyl Pyridin-3-yl) -3-styrylpyridine (MR31351)
1H−NMR(CDCl3):δ8.82(d,1H,J=2.2Hz),8,66(d,1H,J=2.2Hz),8.04(d,1H,J=2.2Hz),7.99(d,1H,J=2.2Hz),7.39(d,2H,J=7.3Hz),7.32−7.25(m,3H),7.18(s,1H),7.14(d,1H,J=16Hz),7.12(s,1H),7.10(d,1H,J=16Hz),3.69(s,3H,CH3),3.65(s,3H,CH3),2.47(s,3H,CH3).
MS(EI):501.13[M+]*,503.12[M++2]*,505.32[M++4]*.
1 H-NMR (CDCl 3 ): δ 8.82 (d, 1H, J = 2.2 Hz), 8, 66 (d, 1H, J = 2.2 Hz), 8.04 (d, 1H, J = 2) .2 Hz), 7.99 (d, 1 H, J = 2.2 Hz), 7.39 (d, 2 H, J = 7.3 Hz), 7.32-7.25 (m, 3 H), 7.18 (S, 1H), 7.14 (d, 1H, J = 16 Hz), 7.12 (s, 1H), 7.10 (d, 1H, J = 16 Hz), 3.69 (s, 3H, CH 3), 3.65 (s, 3H , CH 3), 2.47 (s, 3H, CH 3).
MS (EI): 501.13 [M + ] * , 503.12 [M + +2] * , 505.32 [M + +4] * .
実施例7:3−メチル−2−(4−シアノフェニル)−5−(5−(4−シアノフェニル)−3−スチリルピリジン−2−イル)ピリジン(MR30854) Example 7: 3-Methyl-2- (4-cyanophenyl) -5- (5- (4-cyanophenyl) -3-styrylpyridin-2-yl) pyridine (MR30854)
1H NMR(400MHz,CDCl3):δ8.88(d,J=2.2,1H,H2’),8.85(d,J=2.2,1H,H6),8.24(d,J=2.2,1H,H4),8.04(d,J=2.2,1H,H4’),7.79(dd,J=8.3,1.9,4H),7.74(dd,J=8.5,2.0,4H),7.45(d,J=8.0,2H,Hstyr),7.35(d,J=8.1,2H,Hstyr),7.31(d,J=7.3,1H,Hstyr),7.17(d,J=16.3,2H,CH=CH),2.49(s,3H,CH3). 1 H NMR (400 MHz, CDCl 3 ): δ 8.88 (d, J = 2.2, 1H, H2 ′), 8.85 (d, J = 2.2, 1H, H6), 8.24 (d , J = 2.2, 1H, H4), 8.04 (d, J = 2.2, 1H, H4 ′), 7.79 (dd, J = 8.3, 1.9, 4H), 7 .74 (dd, J = 8.5, 2.0, 4H), 7.45 (d, J = 8.0, 2H, Hstyr), 7.35 (d, J = 8.1, 2H, Hstyr) ), 7.31 (d, J = 7.3, 1H, Hstyr), 7.17 (d, J = 16.3, 2H, CH = CH), 2.49 (s, 3H, CH 3 ).
実施例8:5−(3,4,5−トリメトキシフェニル)−2−(6−(3,4,5−トリメトキシフェニル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR30847) Example 8: 5- (3,4,5-trimethoxyphenyl) -2- (6- (3,4,5-trimethoxyphenyl) -5-methylpyridin-3-yl) -3-styrylpyridine ( MR30847)
1H NMR(400MHz,CDCl3):δ8.83(s,1H,H6),8.80(s,1H,H2’),8.16(s,1H,H4),7.99(s,1H,H4’),7.49(d,J=7.1,2H,Hstyr),7.35(dd,J=7.6,6.8,2H,Hstyr),7.31(d,J=7.3,1H,Hstyr),7.28(d,J=15.6,1H,CH=CH),7,21(d,J=15.6,1H,CH=CH),6.86(s,2H),6,84(s,2H),3.99(s,6H,CH3O−meta),3,93(s,3H,CH3O−para),3,91(s,6H,CH3O−meta’),3,82(s,3H,CH3O−para’),2,50(s,3H,CH3). 1 H NMR (400 MHz, CDCl 3 ): δ 8.83 (s, 1H, H6), 8.80 (s, 1H, H2 ′), 8.16 (s, 1H, H4), 7.99 (s, 1H, H4 ′), 7.49 (d, J = 7.1, 2H, Hstyr), 7.35 (dd, J = 7.6, 6.8, 2H, Hstyr), 7.31 (d, J = 7.3, 1H, Hstyr), 7.28 (d, J = 15.6, 1H, CH = CH), 7, 21 (d, J = 15.6, 1H, CH = CH), 6 .86 (s, 2H), 6, 84 (s, 2H), 3.99 (s, 6H, CH 3 O-meta), 3 , 93 (s, 3H, CH 3 O-para), 3 , 91 (s, 6H, CH 3 O -meta '), 3,82 (s, 3H, CH 3 O-para'), 2,50 (s, 3H, CH 3).
実施例9:2−(3,4−ジメトキシフェニル)−5−(5−(3,4−ジメトキシフェニル)−3−スチリルピリジン−2−イル)−3−メチルピリジン(MR30846) Example 9: 2- (3,4-Dimethoxyphenyl) -5- (5- (3,4-dimethoxyphenyl) -3-styrylpyridin-2-yl) -3-methylpyridine (MR30846)
1H NMR(400MHz,CDCl3):δ8.84(s,1H,H6 ),8.80(s,1H,H2’),8.17(s,1H,H4),7.98(s,1H,H4’),7.48(d,J=6.8,2H,Hstyr),7.36(dd,J=7.8,7.1,2H,Hstyr),7.30(d,J=8.3,1H,Hstyr),7.28(d,J=16.4,1H,CH=CH),7,27−7.21(m,4H),7.18(d,J=15.9,1H,CH=CH),7.04(d,J=8.3,1H),6.98(d,J=8.3,1H),4.01(s,3H,CH3O−meta’),3,97(s,9H),2,50(s,3H,CH3). 1 H NMR (400 MHz, CDCl 3 ): δ 8.84 (s, 1H, H6), 8.80 (s, 1H, H2 ′), 8.17 (s, 1H, H4), 7.98 (s, 1H, H4 ′), 7.48 (d, J = 6.8, 2H, Hstyr), 7.36 (dd, J = 7.8, 7.1, 2H, Hstyr), 7.30 (d, J = 8.3, 1H, Hstyr), 7.28 (d, J = 16.4, 1H, CH = CH), 7, 27-7.21 (m, 4H), 7.18 (d, J = 15.9, 1H, CH = CH), 7.04 (d, J = 8.3, 1H), 6.98 (d, J = 8.3, 1H), 4.01 (s, 3H, CH 3 O-meta '), 3,97 (s, 9H), 2,50 (s, 3H, CH 3).
実施例10:4−(3−メチル−5−(5−(ピリジン−4−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)ピリジン(MR31350) Example 10: 4- (3-Methyl-5- (5- (pyridin-4-yl) -3-styrylpyridin-2-yl) pyridin-2-yl) pyridine (MR31350)
1H−NMR(CDCl3):δ8.85(d,1H,J=2.2Hz),8,80(d,1H,J=1.9Hz),8.73−8.71(dd,2H,J=1.7Hz,J=4.5Hz),8.70−8.68(dd,2H,J=1.7Hz,J=4.5Hz),8.21(d,1H,J=2.2Hz),7.97(d,1H,J=1.9Hz),7.58−7.57(dd,2H,J=1.7Hz,J=4.5Hz),7.48−7.47(dd,2H,J=1.7Hz,J=4.5Hz),7.41(d,2H,J=6.8Hz),7.32−7.29(m,2H),7.26−7.25(m,1H),7.23−7.16(m,2H,CH=CH),2.43(s,3H,CH3).
MS(EI):427.37[M+]*
1 H-NMR (CDCl 3 ): δ 8.85 (d, 1H, J = 2.2 Hz), 8, 80 (d, 1H, J = 1.9 Hz), 8.73-8.71 (dd, 2H) , J = 1.7 Hz, J = 4.5 Hz), 8.70-8.68 (dd, 2H, J = 1.7 Hz, J = 4.5 Hz), 8.21 (d, 1H, J = 2) .2 Hz), 7.97 (d, 1H, J = 1.9 Hz), 7.58-7.57 (dd, 2H, J = 1.7 Hz, J = 4.5 Hz), 7.48-7. 47 (dd, 2H, J = 1.7 Hz, J = 4.5 Hz), 7.41 (d, 2H, J = 6.8 Hz), 7.32-7.29 (m, 2H), 7.26 -7.25 (m, 1H), 7.23-7.16 (m, 2H, CH = CH), 2.43 (s, 3H, CH3).
MS (EI): 427.37 [M + ] *
実施例11:3−メチル−2−フェニル−5−(5−フェニル−3−スチリルピリジン−2−イル)ピリジン(MR30814) Example 11: 3-Methyl-2-phenyl-5- (5-phenyl-3-styrylpyridin-2-yl) pyridine (MR30814)
13C NMR(100MHz,CDCl3):δ158.4,153.1,146.9,146.2,140.3,139.7,137.5,136.8,135.9,133.3,132.5(2C),131.7,130.6,129.3(2C),129.2(2C),128.8(2C),128.3(2C),128.2(2C),128.1,127.2(2C),126.8(2C),125.4,20.1.
LCMS(ESI)(m/z):424.55;[M+H+]425.27.
13 C NMR (100 MHz, CDCl 3 ): δ 158.4, 153.1, 146.9, 146.2, 140.3, 139.7, 137.5, 136.8, 135.9, 133.3 132.5 (2C), 131.7, 130.6, 129.3 (2C), 129.2 (2C), 128.8 (2C), 128.3 (2C), 128.2 (2C), 128.1, 127.2 (2C), 126.8 (2C), 125.4, 20.1.
LCMS (ESI) (m / z): 424.55; [M + H <+ >] 425.27.
実施例12:5−(3−メチル−5−(5−(ピリミジン−5−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)ピリミジン(MR31361) Example 12: 5- (3-Methyl-5- (5- (pyrimidin-5-yl) -3-styrylpyridin-2-yl) pyridin-2-yl) pyrimidine (MR31361)
1H−NMR(CDCl3):δ9.33(s,1H),9.30(s,1H),9.10(s,2H),9.07(s,2H),8.90(d,1H,J=1.9Hz),8.88(d,1H J=2.2Hz),8.25(d,1H,J=2.2Hz),8.07(d,1H,J=1.9Hz),7.48(d,2H,J=7Hz),7.40−7.32(m,3H),7.27(d,1H,J=16Hz,CH=CH),7.22(d,1H,J=16Hz,CH=CH),2.53(s,3H,CH3).
MS(EI):429.58[M+]*.
1 H-NMR (CDCl 3 ): δ 9.33 (s, 1H), 9.30 (s, 1H), 9.10 (s, 2H), 9.07 (s, 2H), 8.90 (d , 1H, J = 1.9 Hz), 8.88 (d, 1H J = 2.2 Hz), 8.25 (d, 1H, J = 2.2 Hz), 8.07 (d, 1H, J = 1) .9 Hz), 7.48 (d, 2H, J = 7 Hz), 7.40-7.32 (m, 3H), 7.27 (d, 1H, J = 16 Hz, CH = CH), 7.22. (D, 1H, J = 16 Hz, CH = CH), 2.53 (s, 3H, CH 3 ).
MS (EI): 429.58 [M <+ >] * .
第2及び第3の手順(スキーム2)を、3−メチル−5−(5−フェニル−3−スチリルピリジン−2−イル)−2−(ピリジン−3−イル)ピリジン(MR31348)、3−(6−(5−メチル−6−フェニルピリジン−3−イル)−5−スチリルピリジン−3−イル)ピリジン(MR31349)、3−(3−メチル−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)フェノール(MR31364)、3−(3−メチル−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)フェノール(MR31366),(1Z)−N’−ヒドロキシ−2−(3−(3−メチル−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)フェニル)アセタミジン(MR31367)、5−(3,4−ジメトキシフェニル)−2−(6−(3,4,5−トリメトキシフェニル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR30849)、5−(3,4,5−トリメトキシフェニル)−2−(6−(3,4−ジメトキシフェニル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR30850)の化合物に適用した。 The second and third procedures (Scheme 2) were performed according to 3-methyl-5- (5-phenyl-3-styrylpyridin-2-yl) -2- (pyridin-3-yl) pyridine (MR31348), 3- (6- (5-Methyl-6-phenylpyridin-3-yl) -5-styrylpyridin-3-yl) pyridine (MR31349), 3- (3-methyl-5- (5- (pyridin-3-yl) ) -3-styrylpyridin-2-yl) pyridin-2-yl) phenol (MR31364), 3- (3-methyl-5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) ) Pyridin-2-yl) phenol (MR31366), (1Z) -N′-hydroxy-2- (3- (3-methyl-5- (5- (pyridin-3-yl) -3-styrylpyridine-2) -Il) Pyridi -2-yl) phenyl) acetamidine (MR31367), 5- (3,4-dimethoxyphenyl) -2- (6- (3,4,5-trimethoxyphenyl) -5-methylpyridin-3-yl)- 3-styrylpyridine (MR30849), 5- (3,4,5-trimethoxyphenyl) -2- (6- (3,4-dimethoxyphenyl) -5-methylpyridin-3-yl) -3-styrylpyridine Applied to the compound of (MR30850).
実施例13:5−(3,4,5−トリメトキシフェニル)−2−(6−(3,4−ジメトキシフェニル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR30850) Example 13: 5- (3,4,5-trimethoxyphenyl) -2- (6- (3,4-dimethoxyphenyl) -5-methylpyridin-3-yl) -3-styrylpyridine (MR30850)
1H NMR(400MHz,CDCl3):δ8.83(d,J=2.2,1H,H6),8.80(d,J=2.2,1H,H2’),8.16(d,J=2.4,1H,H4),7.98(d,J=1.7,1H,H4’),7.49(d,J=7.1,2H,Ha),7.36(dd,J=7,6,7.1,2H,Hb),7.30(d,J=6.8,1H,Hc),7.21(d,J=17.8,1H,CH=CH),7.20(d,J=17.8,1H,CH=CH),7.20(d,J=8.3,1H),7.19(d,J=8.0,1H),6.98(d,J=8.3,1H),6.86(s,2H),3.99(s,6H),3.97(s,3H),3.96(s,3H),3.94(s,3H),2.50(s,3H,CH3). 1 H NMR (400 MHz, CDCl 3 ): δ 8.83 (d, J = 2.2, 1H, H6), 8.80 (d, J = 2.2, 1H, H2 ′), 8.16 (d , J = 2.4, 1H, H4), 7.98 (d, J = 1.7, 1H, H4 ′), 7.49 (d, J = 7.1, 2H, Ha), 7.36. (Dd, J = 7, 6, 7.1, 2H, Hb), 7.30 (d, J = 6.8, 1H, Hc), 7.21 (d, J = 17.8, 1H, CH = CH), 7.20 (d, J = 17.8, 1H, CH = CH), 7.20 (d, J = 8.3, 1H), 7.19 (d, J = 8.0, 1H), 6.98 (d, J = 8.3, 1H), 6.86 (s, 2H), 3.99 (s, 6H), 3.97 (s, 3H), 3.96 (s) , 3H), 3.94 (s, 3H), 2.50 (s, 3H, C 3).
実施例14:5−(3,4−ジメトキシフェニル)−2−(6−(3,4,5−トリメトキシフェニル)−5−メチルピリジン−3−イル)−3−スチリルピリジン(MR30849) Example 14: 5- (3,4-Dimethoxyphenyl) -2- (6- (3,4,5-trimethoxyphenyl) -5-methylpyridin-3-yl) -3-styrylpyridine (MR30849)
1H NMR(400MHz,CDCl3):δ8.84(d,J=2.2,1H,H6),8.79(d,J=2.2,1H,H2’),8.17(d,J=2.2,1H,H4),7.99(d,J=2.0,1H,H4’),7.48(d,J=7.3,2H,Hstyr),7.35(dd,J=7.8,6.8,2H,Hstyr),7.30(d,J=7.1,1H,Hstyr),7.27(d,J=2.2,1H),7.27(d,J=16,1H,CH=CH),7.23(d,J=16.2,1H,CH=CH),7.19(d,J=2.2,1H),6.84(s,3H),4.01(s,3H),3.97(s,3H),3.93(s,6H),3.91(s,3H),2.50(s,3H,CH3). 1 H NMR (400 MHz, CDCl 3 ): δ 8.84 (d, J = 2.2, 1H, H6), 8.79 (d, J = 2.2, 1H, H2 ′), 8.17 (d , J = 2.2, 1H, H4), 7.9 (d, J = 2.0, 1H, H4 ′), 7.48 (d, J = 7.3, 2H, Hstyr), 7.35. (Dd, J = 7.8, 6.8, 2H, Hstyr), 7.30 (d, J = 7.1, 1H, Hstyr), 7.27 (d, J = 2.2, 1H), 7.27 (d, J = 16, 1H, CH = CH), 7.23 (d, J = 16.2, 1H, CH = CH), 7.19 (d, J = 2.2, 1H) , 6.84 (s, 3H), 4.01 (s, 3H), 3.97 (s, 3H), 3.93 (s, 6H), 3.91 (s, 3H), 2.50 ( s, 3H, CH 3).
実施例15:(1Z)−N’−ヒドロキシ−2−(3−(3−メチル−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)フェニル)アセタミジン(MR31367) Example 15: (1Z) -N′-hydroxy-2- (3- (3-methyl-5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) pyridin-2-yl ) Phenyl) acetamidine (MR31367)
1H−NMR(CDCl3):δ8.98(d,1H,J=1.96Hz),8.87(d,1H,J=2.2Hz),8.82(d,1H,J=2.2Hz),8.72(d,1H,J=1.96Hz),8.24(d,1H,J=2.2Hz),8.02−8.00(m,2H),7.55−7.43(m,7H),7.36−7.20(m,4H),4.58(bs,1H,NH2),3.56(s,2H,CH2),2.46(s,3H,CH3).
MS(EI):498.55[M+]*
1 H-NMR (CDCl 3 ): δ 8.98 (d, 1H, J = 1.96 Hz), 8.87 (d, 1H, J = 2.2 Hz), 8.82 (d, 1H, J = 2) .2 Hz), 8.72 (d, 1 H, J = 1.96 Hz), 8.24 (d, 1 H, J = 2.2 Hz), 8.02-8.00 (m, 2 H), 7.55 -7.43 (m, 7H), 7.36-7.20 (m, 4H), 4.58 (bs, 1H, NH 2), 3.56 (s, 2H, CH 2), 2.46 (s, 3H, CH 3) .
MS (EI): 498.55 [M + ] *
実施例16:3−(3−メチル−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)フェノール(MR31366) Example 16: 3- (3-Methyl-5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) pyridin-2-yl) phenol (MR31366)
1H−NMR(CD3OD):δ10.5(bs,1H,COOH),9.02(d,1H,J=1.96Hz),8.90(d,1H,J=2.2Hz),8.68(d,1H,J=2.2Hz),8.66−8.64(dd,1H,J=1.2Hz,J=4.6Hz),8.56(d,1H,J=2.2Hz),8.33−8.31(dd,1H,J=1.3Hz,J=4.6Hz),8.07(d,1H,J=2.2Hz),7.63−7.62(m,1H),7.53−7.48(m,5H),7.37−7.33(m,2H),7.29−7.21(m,2H),3.71(s,2H,CH2),2.44(s,3H,CH3).
MS(EI):484.54[M+]*
1 H-NMR (CD 3 OD): δ 10.5 (bs, 1H, COOH), 9.02 (d, 1H, J = 1.96 Hz), 8.90 (d, 1H, J = 2.2 Hz) , 8.68 (d, 1H, J = 2.2 Hz), 8.66-8.64 (dd, 1H, J = 1.2 Hz, J = 4.6 Hz), 8.56 (d, 1H, J = 2.2 Hz), 8.33-8.31 (dd, 1H, J = 1.3 Hz, J = 4.6 Hz), 8.07 (d, 1H, J = 2.2 Hz), 7.63- 7.62 (m, 1H), 7.53-7.48 (m, 5H), 7.37-7.33 (m, 2H), 7.29-7.21 (m, 2H), 3. 71 (s, 2H, CH 2 ), 2.44 (s, 3H, CH 3).
MS (EI): 484.54 [M + ] *
実施例17:3−(3−メチル−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン−2−イル)フェノール(MR31364) Example 17: 3- (3-Methyl-5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) pyridin-2-yl) phenol (MR31364)
1H−NMR(CDCl3):δ8.98(d,1H,J=1.96Hz),8.86(d,1H,J=1.96Hz),8.78(d,1H,J=1.96Hz),8.72−8.71(m,1H) 8.26(d,1H,J=2.2Hz),8.03−7.99(m,3H),7.51−7.46(m,3H),7.35−7.32(m,2H),7.31−7.20(m,4H),7.07(d,1H,J=7.56Hz),6.93(s,1H),6−84−6.81(dd,1H,J=1.6Hz,J=7.56Hz),2.45(s,CH3),1.77(bs,1H,OH)
MS(EI):442.41[M+]*
1 H-NMR (CDCl 3 ): δ 8.98 (d, 1H, J = 1.96 Hz), 8.86 (d, 1H, J = 1.96 Hz), 8.78 (d, 1H, J = 1) .96 Hz), 8.72-8.71 (m, 1H) 8.26 (d, 1H, J = 2.2 Hz), 8.03-7.99 (m, 3H), 7.51-7. 46 (m, 3H), 7.35-7.32 (m, 2H), 7.31-7.20 (m, 4H), 7.07 (d, 1H, J = 7.56 Hz), 6. 93 (s, 1H), 6-84-6.81 (dd, 1H, J = 1.6 Hz, J = 7.56 Hz), 2.45 (s, CH 3 ), 1.77 (bs, 1H, OH)
MS (EI): 442.41 [M + ] *
実施例18:3−(6−(5−メチル−6−フェニルピリジン−3−イル)−5−スチリルピリジン−3−イル)ピリジン(MR31349) Example 18: 3- (6- (5-Methyl-6-phenylpyridin-3-yl) -5-styrylpyridin-3-yl) pyridine (MR31349)
1H−NMR(CDCl3):δ8.90(d,1H,J=1.9Hz),8,79(d,1H,J=2.2Hz),8.75(d,1H,J=2.2Hz),8.64−8.62(dd,1H,J=1.2Hz,J=4.7Hz),8.15(d,1H,J=2.2Hz),7.94−7.91(m,2H),7.55(d,2H,J=7Hz),7.44−7.33(m,6H),7.29−7.26(m,2H),7.23−7.19(m,2H),7.14(d,1H,J=16Hz,CH=CH),2.42(s,3H,CH3).
MS(EI):426.42[M+]*
1 H-NMR (CDCl 3 ): δ 8.90 (d, 1H, J = 1.9 Hz), 8, 79 (d, 1H, J = 2.2 Hz), 8.75 (d, 1H, J = 2) .2 Hz), 8.64-8.62 (dd, 1H, J = 1.2 Hz, J = 4.7 Hz), 8.15 (d, 1H, J = 2.2 Hz), 7.94-7. 91 (m, 2H), 7.55 (d, 2H, J = 7 Hz), 7.44-7.33 (m, 6H), 7.29-7.26 (m, 2H), 7.23- 7.19 (m, 2H), 7.14 (d, 1H, J = 16 Hz, CH = CH), 2.42 (s, 3H, CH3).
MS (EI): 426.42 [M + ] *
実施例19:3−メチル−5−(5−フェニル−3−スチリルピリジン−2−イル)−2−(ピリジン−3−イル)ピリジン(MR31348) Example 19: 3-Methyl-5- (5-phenyl-3-styrylpyridin-2-yl) -2- (pyridin-3-yl) pyridine (MR31348)
1H−NMR(CDCl3):δ8.90(d,1H,J=1.9Hz),8,88(d,1H,J=2.2Hz),8.86(d,1H,J=1.9Hz),8.68−8.67(dd,1H,J=1.7Hz,J=4.8Hz),8.24(d,1H,J=1.9Hz),8.03(d,1H,J=1.7Hz),7.98−7.97(m,1H),7.72(d,2H,J=8.3Hz),7.57−7.53(m,2H),7.49−7.46(m,4H),7.38−7.34(m,2H),7.31−7.29(m,1H),7.27(d,1H,J=16.6Hz),7.22(d,1H,J=16.6Hz),2.50(s,3H,CH3).
MS(EI):426.58[M+]*
1 H-NMR (CDCl 3 ): δ 8.90 (d, 1H, J = 1.9 Hz), 8, 88 (d, 1H, J = 2.2 Hz), 8.86 (d, 1H, J = 1) .9 Hz), 8.68-8.67 (dd, 1 H, J = 1.7 Hz, J = 4.8 Hz), 8.24 (d, 1 H, J = 1.9 Hz), 8.03 (d, 1H, J = 1.7 Hz), 7.98-7.97 (m, 1H), 7.72 (d, 2H, J = 8.3 Hz), 7.57-7.53 (m, 2H), 7.49-7.46 (m, 4H), 7.38-7.34 (m, 2H), 7.31-7.29 (m, 1H), 7.27 (d, 1H, J = 16 .6 Hz), 7.22 (d, 1H, J = 16.6 Hz), 2.50 (s, 3H, CH3).
MS (EI): 426.58 [M + ] *
II.式(I)の化合物の生物活性 II. Biological activity of compounds of formula (I)
II.A.材料&方法
試験化合物
(ヘテロ)芳香族オリゴ系を実施例Iに記載したように合成し、クロマトグラフィー(固定相としてフラッシュシリカゲル60、Merck社製[0.063〜0.200mm]を使用したカラム)により精製した。
II. A. Materials & Methods Test compounds Columns using (hetero) aromatic oligo systems synthesized as described in Example I and using chromatography (flash silica gel 60 as stationary phase, Merck [0.063-0.200 mm]. ).
ABT−737はSelleckchen社(テキサス州ヒューストン、米国)から入手し、ジメチルスルホキシド(DMSO)はSigma−Aldrich社(Saint−Quentin Fallavier、フランス)から入手した。 ABT-737 was obtained from Sellecken (Houston, Texas, USA) and dimethyl sulfoxide (DMSO) was obtained from Sigma-Aldrich (Saint-Quentin Fallavier, France).
これらの化合物は通常、−20℃にてDMSO保存溶液として保管された。 These compounds were usually stored as DMSO stock solutions at -20 ° C.
細胞培養
ヒト卵巣癌OAW42細胞株をヒト卵巣腺癌から樹立し、ECACC(Sigma−Aldrich社、Saint−Quentin Fallavier、フランス)から入手した。当該細胞株は、4500mg/グルコース、2mMのGlutamax、1mMのピルビン酸ナトリウム、10%ウシ胎児血清、33mMの重炭酸ナトリウム(Gibco BRL社、リヨン、フランス)、及び20IU/組換えヒトインスリン(Lilly社、Suresnes、フランス)が添加されたDMEM培地で培養された。
Cell Culture The human ovarian cancer OAW42 cell line was established from human ovarian adenocarcinoma and obtained from ECACC (Sigma-Aldrich, Saint-Quentin Fallavier, France). The cell lines are 4500 mg / glucose, 2 mM Glutamax, 1 mM sodium pyruvate, 10% fetal calf serum, 33 mM sodium bicarbonate (Gibco BRL, Lyon, France), and 20 IU / recombinant human insulin (Lilly) , Suresnes, France) in DMEM medium supplemented.
ヒト卵巣癌SKOV3細胞株をヒト卵巣腺癌から樹立し、ヒト悪性中皮腫細胞株NCI−H28及びヒト肺癌細胞株A549と同様にアメリカ合衆国培養細胞株統保存機関(ヴァージニア州マナッサス、米国)から入手した。 The human ovarian cancer SKOV3 cell line was established from human ovarian adenocarcinoma and obtained from the American Cultured Cell Line Conservation Organization (Manassas, Virginia, USA) as well as the human malignant mesothelioma cell line NCI-H28 and human lung cancer cell line A549. did.
IGROV1細胞株は、J.Benard博士(Institut G. Roussy、Villejuif、フランス)によりご提供いただいた。これらの細胞株は、2mMのGlutamax(商標)、25mMのHEPES、10%ウシ胎児血清、及び33mMの重炭酸ナトリウム(Fisher Scientific社、Illkirch、フランス)が添加されたRPMI1640培地で培養された。 IGROV1 cell line is described in J. Org. Courtesy of Dr. Benard (Institute G. Roussy, Villejuif, France). These cell lines were cultured in RPMI 1640 medium supplemented with 2 mM Glutamax ™, 25 mM HEPES, 10% fetal calf serum, and 33 mM sodium bicarbonate (Fisher Scientific, Illkirch, France).
IGROV1(IGROV1−R10)及びOVW42(OAW42−R)細胞株の生体外化学療法抵抗性モデルは、シスプラチン投与の臨床試験実施計画書[Poulainら(1998)Int J Cancer 78、454〜463、Villedieuら,(2007)Gynecol Oncol.105(1)、31〜44]を模することによって事前に入手した。 In vitro chemoresistance models of the IGROV1 (IGROV1-R10) and OVW42 (OAW42-R) cell lines are described in clinical trial implementation plans for cisplatin administration [Poulain et al. (1998) Int J Cancer 78, 454-463, Villedieu et al. (2007) Gynecol Oncol. 105 (1), 31-44], obtained in advance.
細胞を、5%CO2加湿雰囲気中において37℃で維持し、トリプシン処理により週2回剥離した。 Cells were maintained at 37 ° C. in a 5% CO 2 humidified atmosphere and detached by trypsinization twice a week.
処理
指数関数的に増殖する細胞を、以下に記述されるようにsiRNAでトランスフェクションし、48時間後、細胞をDMSO中に溶解させた(ヘテロ)芳香族オリゴ系(10、25、又は50μM)(全体積の<0.1%)に更に4〜24時間連続して曝露した。
Treatment Exponentially growing cells were transfected with siRNA as described below, and after 48 hours the cells were lysed in DMSO (hetero) aromatic oligo systems (10, 25, or 50 μM) (<0.1% of the total volume) was further exposed for 4-24 hours continuously.
遺伝子サイレンシング
siRNAはEurogentec社(リエージュ、ベルギー)により合成及びアニーリングされた。配列は以下の通りである。
Bcl−xL siRNAアンチセンス(siXL1):5’−auuggugagucggaucgcatt−3’(配列番号1)、
Mcl−1 siRNA(siMCL1):5’−gugccuuuguggcuaaacatt−3’(配列番号2)、
対照siRNA(siCONT):5’−gacguaaacggccacaagutt−3’(配列番号3)。
Gene silencing siRNA was synthesized and annealed by Eurogentec (Liege, Belgium). The sequence is as follows.
Bcl-x L siRNA antisense (siXL1): 5′-auuggugagucgaucgcatt-3 ′ (SEQ ID NO: 1),
Mcl-1 siRNA (siMCL1): 5′-gucccuuuguggcuaaaactt-3 ′ (SEQ ID NO: 2),
Control siRNA (siCONT): 5'-gacguaaaacggccacaagutt-3 '(SEQ ID NO: 3).
対照siRNAはいかなる関連するヒト遺伝子とも一切相同性を有していない。トランスフェクション時に30〜50%の培養密度に達する前日に細胞を25cm2フラスコに播種した。トランスフェクションINTERFERin(商標)試薬(Polyplus Transfection社、ストラスブール、フランス)を、Opti−MEM(登録商標)低血清培地(Invitrogen社、Cergy−Pontoise、フランス)で希釈したsiRNAに添加し、室温で15分間複合体を形成させてから、細胞に適用した。フラスコ中の最終siRNA濃度は20nMであった。 The control siRNA has no homology with any related human gene. Cells were seeded into 25 cm 2 flasks the day before reaching a culture density of 30-50% at the time of transfection. Transfection INTERFERIN ™ reagent (Polyplus Transfection, Strasbourg, France) is added to siRNA diluted in Opti-MEM® low serum medium (Invitrogen, Cergy-Pontoise, France) for 15 minutes at room temperature. Complexes were formed and then applied to the cells. The final siRNA concentration in the flask was 20 nM.
BRETアッセイ
ヒーラー細胞を6ウェルプレートに接種し、200ng/ウェルのBRETドナーをコードするプラスミドpRLuc−Bax、pRLuc−Puma、又はpRLuc−Noxa、及び1μg/ウェルのBRETアクセプタをコードするpeYFP−Bcl−xL又はpeYFP−Mcl−1を用いて(又は対照としてpCMV−Bcl−xL又はpCMV−Mcl−1を用いて)トランスフェクションした。トランスフェクションの24時間後、細胞をトリプシン処理し、白色96ウェル平底プレートに再び播種し、もう1日インキュベートし、その後、16時間10μMの薬物で処理した。最終濃度5μMのルシフェラーゼ基質であるセレンテラジンH(Uptima社)を添加した後に、485nm及び530nmの光放射をMithras蛍光/ルミネッセンス検出器LB940(Berthold社)を使用して連続的に測定した。BRET比は記載されている通りに計算した[Terrillonら(2003)Mol Endocrinol 17、677〜691、Voら(2012)Eur J Med Chem.、286〜93]。
BRET assay Healer cells are seeded in 6-well plates and peYFP-Bcl-x encoding plasmids pRLuc-Bax, pRLuc-Puma, or pRLuc-Numa, and 1 μg / well of BRET acceptor encoding 200 ng / well of BRET donor. Transfected with L or peYFP-Mcl-1 (or with pCMV-Bcl-x L or pCMV-Mcl-1 as a control). Twenty-four hours after transfection, cells were trypsinized, replated into white 96-well flat bottom plates, incubated for another day, and then treated with 10 μM drug for 16 hours. After addition of coelenterazine H (Uptima), a luciferase substrate at a final concentration of 5 μM, light emission at 485 nm and 530 nm was measured continuously using a Mitras fluorescence / luminescence detector LB940 (Berthold). BRET ratios were calculated as described [Terrillon et al. (2003) Mol Endocrinol 17, 677-691, Vo et al. (2012) Eur J Med Chem. 286-93].
リアルタイム細胞活性アッセイ
化合物により媒介される細胞毒性は、リアルタイム細胞アナライザマルチプレート(RTCA MP)機器、xCELLigenceシステム(Roche Applied Science社、マンハイム、ドイツ)を使用してモニターした。このシステムは、組織培養E−plates View(Roche社)の底部に組み込まれたくし形マイクロ電極間の電気インピーダンスを測定してリアルタイムで細胞事象をモニターする。電極センサに付着した細胞の数及びサイズの増大は、インピーダンスの増加につながり、これよりプロットに表示される細胞インデックス値(CI)が導かれる。従って、このインデックスは、Keら(Methods Mol Biol 740(2011),33〜43)により記述されるように、細胞生存率の変化を反映する。要約すると、96ウェルE−Plateには3×103細胞/ウェルが播種され、これを組織培養インキュベータ内に配置されたRTCA MPに置いたが、細胞は処理前に24時間増殖させた。インピーダンスは処理終了まで連続して測定された。ウェル複製の標準偏差はRTCAソフトウェアを用いて分析した。
Real-time Cell Activity Assay Compound-mediated cytotoxicity was monitored using a real-time cell analyzer multiplate (RTCAM MP) instrument, xCELLligence system (Roche Applied Science, Mannheim, Germany). This system monitors cellular events in real time by measuring the electrical impedance between comb microelectrodes built into the bottom of tissue culture E-plates View (Roche). An increase in the number and size of cells attached to the electrode sensor leads to an increase in impedance, which leads to the cell index value (CI) displayed in the plot. This index thus reflects changes in cell viability as described by Ke et al. (Methods Mol Biol 740 (2011), 33-43). In summary, 96-well E-Plates were seeded with 3 × 10 3 cells / well and placed in RTCAM MP placed in a tissue culture incubator, but the cells were allowed to grow for 24 hours prior to treatment. Impedance was measured continuously until the end of processing. The standard deviation of well replication was analyzed using RTCA software.
アポトーシスアッセイ
DAPIを用いた核染色によるアポトーシス細胞の形態的特徴付け
処理後、浮遊(detached)細胞及び接着細胞の両方をトリプシン処理後にプールし、ポリリシンでコートしたスライドガラスを細胞塗沫遠心により塗沫し、エタノール/クロロホルム/酢酸(6:3:1)の溶液で固定した。次に、調製物を室温で15分間1μg/mlのDAPI溶液(Boehringer Mannheim−Roche社、マンハイム、ドイツ)と共にインキュベートし、蒸留水中で洗浄し、Mowiol(Calbiochem社)中でカバーガラス下に取り付け、蛍光顕微鏡(BX51、Olympus社、Rungis、フランス)で分析した。
Apoptosis assay Morphological characterization of apoptotic cells by nuclear staining with DAPI After treatment, both detached and adherent cells are pooled after trypsinization and a glass slide coated with polylysine is smeared by cell smear centrifugation And fixed with a solution of ethanol / chloroform / acetic acid (6: 3: 1). The preparation is then incubated with 1 μg / ml DAPI solution (Boehringer Mannheim-Roche, Mannheim, Germany) for 15 minutes at room temperature, washed in distilled water and mounted under a coverslip in Mowiol (Calbiochem) Analysis was performed with a fluorescence microscope (BX51, Olympus, Rungis, France).
フローサイトメトリーによる細胞周期分析
製造業者(Roche Diagnostic社、インディアナポリス、米国)に推奨されるように、接着細胞及び浮遊細胞をプールし、1X PBSで洗浄し、5分間200gで遠心分離にかけ、その後アネキシンV、ヨウ化プロピジウム、又はその両方により染色した。要約すると、100μlのアネキシンV−FITC又はヨウ化プロピジウム又はその両方を細胞ペレット(106細胞)に添加し、暗い場所で室温にて15分間インキュベートした。次に、500μlの試料緩衝液を懸濁液に添加し、この懸濁液はGalliosフローサイトメータ(Beckman Coulter社、Roissy、フランス)を使用して分析し、細胞周期分布はKaluza Acquisitionソフトウェア(Beckman Coulter社)を使用して決定した。
Cell cycle analysis by flow cytometry As recommended by the manufacturer (Roche Diagnostics, Indianapolis, USA), adherent and floating cells are pooled, washed with 1 × PBS, centrifuged at 200 g for 5 minutes, and then Stained with Annexin V, propidium iodide, or both. In summary, 100 μl of annexin V-FITC or propidium iodide or both were added to the cell pellet (10 6 cells) and incubated for 15 minutes at room temperature in the dark. Next, 500 μl of sample buffer was added to the suspension, which was analyzed using a Gallios flow cytometer (Beckman Coulter, Roissy, France) and the cell cycle distribution was analyzed by Kaluza Acquisition software (Beckman (Coulter).
細胞抽出物の調製及びウエスタンブロット分析
細胞は氷冷PBSを用いてすすぎ、溶解緩衝液[RIPA:NaCl 150mM、Tris(pH8)50mM、Triton X100 1%、PMSF 4mM、EDTA 5mM、NaF 10mM、NaPPi 10mM、Na3OV4 1mM、アプロチニン 0.5μl/ml、及び4.6ml超純水]中に懸濁させ、30分間氷上でインキュベートした。溶解物を遠心分離(13200g、10分間、4℃)後に回収し、タンパク質濃度をBradfordアッセイ(Bio−Rad社、ハーキュリーズ、米国)を使用して決定した。20μgのタンパク質を、4〜12%グラジエントポリアクリルアミドゲル(4−12% gradient polyacrylamide gel)(Invitrogen社、Cergy−Pontoise、フランス)を使用したSDS−PAGEによって分離し、Hybond−PVDFメンブレン(Amersham社、Orsay、フランス)に転写した。室温にて0.1%(v/v)Tween20(T−TBS)を含む5%(w/v)脱脂粉乳/TBSで非特異的結合部位を1時間ブロックした後、メンブレンを以下のウサギ単クローン抗体、即ち、PARP、カスパーゼ−3、及びBcl−xL、Bim(Cell Signaling Technology社、Ozyme社、Saint−Quentin−en−Yvelines、フランス)、Mcl−1(Santa Cruz社、Le Perray−en−Yvelines、フランス)、HSP−70、Noxa(Calbiochem社、Fontenay−sous−Bois、フランス)、(Cell Signaling社)、及びActin(Sigma−Aldrich社、Saint−Quentin Fallavier、フランス)で4℃にて一晩インキュベートした。次いで、メンブレンをT−TBSで洗浄し、適切なホースラディッシュペルオキシダーゼ標識抗ウサギ又は抗マウス(Amersham社、Orsay、フランス)二次抗体と共に1時間インキュベートした。Luminescent Image Analyzer(GE Healthcare社、Orsay、フランス)を使用して証明を行った。
Preparation of cell extract and Western blot analysis Cells were rinsed using ice-cold PBS, lysis buffer [RIPA: NaCl 150 mM, Tris (pH 8) 50 mM, Triton X100 1%, PMSF 4 mM, EDTA 5 mM, NaF 10 mM, NaPPi 10 mM , Na3OV4 1 mM, aprotinin 0.5 μl / ml, and 4.6 ml ultrapure water] and incubated on ice for 30 minutes. Lysates were collected after centrifugation (13200 g, 10 min, 4 ° C.) and protein concentration was determined using the Bradford assay (Bio-Rad, Hercules, USA). 20 μg of protein was separated by SDS-PAGE using 4-12% gradient polyacrylamide gel (Invitrogen, Cergy-Pontoise, France) and Hybond-PVDF membrane (Amersham, Orsay, France). After blocking non-specific binding sites with 5% (w / v) nonfat dry milk / TBS containing 0.1% (v / v) Tween 20 (T-TBS) at room temperature for 1 hour, the membrane was isolated with the following rabbits alone: monoclonal antibodies, i.e., PARP, caspase-3, and Bcl-x L, Bim (Cell Signaling Technology , Inc., Ozyme Company, Saint-Quentin-en-Yvelines , France), Mcl-1 (Santa Cruz Inc., Le Perray-en -Yvelines, France), HSP-70, Noxa (Calbiochem, Fontenay-sous-Bois, France), (Cell Signaling), and Actin (Sigma-Aldrich, Saint-Quentin Falla) ier, and incubated overnight at 4 ℃ in France). The membrane was then washed with T-TBS and incubated with an appropriate horseradish peroxidase labeled anti-rabbit or anti-mouse (Amersham, Orsay, France) secondary antibody for 1 hour. Certification was performed using a Luminescent Image Analyzer (GE Healthcare, Orsay, France).
透過型電子顕微鏡
細胞を2.5%グルタルアルデヒド/PBS緩衝液で固定し、寒天に含め、セーレンセンの緩衝液ですすぎ、1%四酸化オスミウム/セーレンセンの緩衝液で後固定し、エタノール中で脱水し、EPON樹脂に包埋した。超薄切片を切り出し、酢酸ウラニル及びクエン酸鉛で染色し、JEOL1011透過型電子顕微鏡を使用して観察した。
Transmission electron microscope Cells were fixed with 2.5% glutaraldehyde / PBS buffer, included in agar, rinsed with Selensen buffer, post-fixed with 1% osmium tetroxide / Selensen buffer, and dehydrated in ethanol And embedded in EPON resin. Ultrathin sections were cut out, stained with uranyl acetate and lead citrate, and observed using a JEOL 1011 transmission electron microscope.
II.B.結果
II.B.1.ピリドクラックスの活性(MR29072)
ピリドクラックスはMcl−1/Pumaの相互作用を阻害する。
II. B. Results II. B. 1. Activity of pyridocrax (MR29072)
Pyridocrax inhibits the Mcl-1 / Puma interaction.
図1A及び図1Bに表されているように、ピリドクラックスは、ヒーラー細胞で行われた細胞アッセイ(BRET)においてMcl−1/Puma及びMcl−1/Noxa両方の相互作用を阻害できる。ABT−737はこの相互作用を調節できないのに対して、ピリドクラックスはMcl−1/Pumaの相互作用の劇的な阻害を引き起こした(約50%)。 As represented in FIGS. 1A and 1B, pyridox can inhibit both Mcl-1 / Puma and Mcl-1 / Noxa interactions in a cellular assay (BRET) performed on healer cells. ABT-737 was unable to regulate this interaction, whereas pyridox led to dramatic inhibition of the Mcl-1 / Puma interaction (about 50%).
単剤として、又はsiRNA媒介Bcl−xL阻害と併用したピリドクラックスの効果
Mcl−1阻害剤としてのピリドクラックスの利益を実証するために、Bcl−xLの発現が曝露前48時間のRNA干渉によりサイレンシングされるBcl−xL及びMcl−1の両方に対する選択的添加モデルを使用した。これらのアッセイを行うのに卵巣癌細胞株IGROV1−R10を選択したが、これは、この細胞株がBcl−xL及びMcl−1の同時阻害に非常に敏感である(Brotinら(2010)Int J Cancer 126,885〜895)が、これらの標的の一方だけが阻害されても生存可能なままであるということが先に示されたからである。
Effect of pyridox as a single agent or in combination with siRNA-mediated Bcl-x L inhibition To demonstrate the benefits of pyridox as a Mcl-1 inhibitor, expression of Bcl-x L was 48 hours prior to exposure. A selective loading model for both Bcl-x L and Mcl-1 silenced by RNA interference was used. The ovarian cancer cell line IGROV1-R10 was chosen to perform these assays, which is very sensitive to the simultaneous inhibition of Bcl-x L and Mcl-1 (Brotin et al. (2010) Int J Cancer 126,885-895) was previously shown to remain viable even if only one of these targets is inhibited.
予想通り、ピリドクラックスもBcl−xL標的siRNA(siXL1)もそれぞれ単独では大規模な細胞死を誘導しなかった。これらの条件において、増殖の失速が観察されたが、細胞剥離又は大きなsub−G1ピーク、カスパーゼ3活性化及び凝縮又は断片化された核も観察されなかった(図2A、図2B、図2C)。 As expected, neither pyridox or Bcl-x L targeted siRNA (siXL1) alone induced massive cell death. Under these conditions, growth stall was observed, but no cell detachment or large sub-G1 peak, caspase 3 activation and condensed or fragmented nuclei were observed (FIGS. 2A, 2B, 2C). .
対照的に、それらの併用により、強い細胞剥離、DNA含有量ヒストグラムにおける大きなsub−G1ピーク(50%超)及びアネキシンV陽性細胞の60%分画の出現(図2A)によって示されるように、大規模な細胞死に至った。更に、生存率評価は、この併用が、生細胞数の劇的な減少及び同時に起こる死細胞の増加をもたらすことを示し(図2B)、ウエスタンブロット法は、PARP及びカスパーゼ3の完全な切断を示した。DAPI染色及び電子顕微鏡は、この併用が、アポトーシス細胞死を強く想起する核の凝縮及び断片化をもたらした(2つの作用物質が組み合わされたときにだけ)ことを示した(図2D)。 In contrast, their combination, as shown by strong cell detachment, a large sub-G1 peak (> 50%) in the DNA content histogram and the appearance of a 60% fraction of annexin V positive cells (FIG. 2A), It led to massive cell death. Furthermore, viability assessment shows that this combination results in a dramatic decrease in the number of live cells and a concomitant increase in dead cells (FIG. 2B), and Western blotting shows complete cleavage of PARP and caspase-3. Indicated. DAPI staining and electron microscopy showed that this combination resulted in nuclear condensation and fragmentation strongly reminiscent of apoptotic cell death (only when the two agents were combined) (FIG. 2D).
これらの効果は、25μM濃度のピリドクラックスへの曝露後に最適となるが、10μMでも小さな反応が観察された(データ不図示)。 These effects are optimal after exposure to 25 μM Pyridocrax, but a small response was observed even at 10 μM (data not shown).
この組み合わせの効果の動態試験は、アポトーシスが曝露開始から早くも2〜4時間後に観察される(4時間後にsub−G1分画における事象の37%)ことを示したが、この観察は、BH3類似活性による薬理学的Mcl−1阻害と両立する(図2E)。 A kinetic study of the effect of this combination showed that apoptosis was observed as early as 2-4 hours after the start of exposure (37% of events in the sub-G1 fraction after 4 hours), but this observation was based on BH3 It is compatible with pharmacological Mcl-1 inhibition by similar activity (FIG. 2E).
全体的に、これらの要素は、ピリドクラックスが卵巣癌化学療法抵抗性IGROV1−R10細胞をBcl−xL標的siRNAに対して強力に感作し、それらの組み合わせが大規模なアポトーシスをもたらすことを示す。 Overall, these factors indicate that pyridocrax strongly sensitizes ovarian cancer chemoresistant IGROV1-R10 cells to Bcl-x L target siRNA, and their combination leads to massive apoptosis Indicates.
ピリドクラックスは、様々な癌細胞型をBcl−xL標的siRNAに対して感作する
その他卵巣癌細胞株(図3A)及びその他の癌細胞型(図3B)におけるピリドクラックスとsiXL1との組み合わせの効果を研究した。
Pyridocrax sensitizes various cancer cell types to Bcl-x L- targeted siRNAs Pyridocrax and siXL1 in other ovarian cancer cell lines (Figure 3A) and other cancer cell types (Figure 3B) The effect of the combination was studied.
この併用に対する同様の反応がすべての卵巣癌細胞株、並びに肺癌(A549)及び中皮腫(NCI−H28及びMSTO−211H)細胞株において観察される。 Similar responses to this combination are observed in all ovarian cancer cell lines, and lung cancer (A549) and mesothelioma (NCI-H28 and MSTO-211H) cell lines.
ピリドクラックスは化学療法抵抗性卵巣癌細胞をABT−737に対して感作する
ABT−737はこれまでのところ最も強力なBcl−xL阻害BH3類似分子の1つであり、その卵巣癌細胞に対する反応はMcl−1の阻害により調節されるが、ABT−787とピリドクラックスとの組み合わせの効果を評価した(図4)。siXL1を用いて先に記載される通り、ABT−737もピリドクラックスも単剤では細胞死を引き起こさなかったが、それらの併用により大規模なアポトーシス細胞死がIGROV1−R10及びSKOV3化学療法抵抗性卵巣癌細胞株の両方でもたらされることが観察された。実際に、2種の分子が組み合わせられると、細胞活性はインピーダンス測定(xCELLigence技術)により評価したときに両細胞株において劇的に低下し(図4A及び図4D)、更に、強力な細胞剥離及び重要なsub−G1分画(図4B)並びに完全なPARP及びカスパーゼ3の切断(図4C及び図4D右パネル)が観察される。これらの効果は、同時曝露実験及び連続曝露実験(ピリドクラックス24時間、その後ABT−737)において同様であったことに注目すべきである。更に、観察されたアポトーシスは、細胞がピリドクラックス及びABT−737に曝露されるとほぼすぐに起こり、BH3類似活性が支持されることを示している。
Pyridocrax sensitizes chemoresistant ovarian cancer cells to ABT-737 ABT-737 is one of the most potent Bcl-x L- inhibiting BH3 analogs to date and its ovarian cancer cells Although the response to is regulated by inhibition of Mcl-1, the effect of the combination of ABT-787 and pyridox was evaluated (FIG. 4). As previously described with siXL1, neither ABT-737 nor pyridox did not cause cell death with a single agent, but their combination resulted in massive apoptotic cell death resulting in resistance to IGROV1-R10 and SKOV3 chemotherapy It was observed to occur in both ovarian cancer cell lines. In fact, when the two molecules are combined, cell activity is dramatically reduced in both cell lines when assessed by impedance measurements (xCELLligence technology) (FIGS. 4A and 4D), and further, strong cell detachment and An important sub-G1 fraction (FIG. 4B) and complete PARP and caspase 3 cleavage (FIG. 4C and 4D right panels) are observed. It should be noted that these effects were similar in simultaneous and continuous exposure experiments (Pyridocrax 24 hours, then ABT-737). Furthermore, the observed apoptosis occurs almost immediately when cells are exposed to pyridox and ABT-737, indicating that BH3-like activity is supported.
II.B.2.本発明のその他の化合物の活性
次に、BRETアッセイにおけるMcl−1/Puma相互作用を阻害する能力で選択された化合物を試験して、その細胞形態、細胞周期、PARP切断、及び核形態に対する活性を評価した。結果は以下の表Iに提示される。
II. B. 2. Activity of other compounds of the invention Next, compounds selected for their ability to inhibit the Mcl-1 / Puma interaction in the BRET assay were tested to determine their activity against cell morphology, cell cycle, PARP cleavage, and nuclear morphology. Evaluated. The results are presented in Table I below.
異なる基準の評価 Evaluation of different criteria
細胞剥離
「−」とは、未処理細胞と、試験化合物で処理された細胞との間に差がないことを意味する。
「±」とは、殆どの細胞が支持体から剥離されなかった(10%未満)ことを意味する。
「+」とは、細胞の約20%が支持体から剥離されたことを意味する。
「++」とは、細胞の約半数が支持体から剥離されたことを意味する。
「+++」とは、細胞の大部分が支持体から剥離されたことを意味する。
Cell detachment "-" means that there is no difference between untreated cells and cells treated with a test compound.
“±” means that most cells were not detached from the support (less than 10%).
“+” Means that about 20% of the cells have been detached from the support.
“++” means that about half of the cells have been detached from the support.
“++++” means that most of the cells have been detached from the support.
PRAP切断
「+」とは、PARPの85kDa切断型に対応する小さなバンドがウエスタンブロットで観察可能であることを意味する。このバンドは、細胞が未処理であれば通常存在しないか又は弱いため、観察可能なバンドは110kDaバンドのみである。
「++」とは、PARPの85kDa切断型に対応するバンドがウエスタンブロットではっきりと観察可能であることを意味する。未切断バンド(110kDa)は通常切断バンドと共存する。
「+++」とは、ほぼ完全に切断されたPARPを意味する。100kDaバンドは多くの場合、85kDa形態のため消失した。
PRAP cleavage “+” means that a small band corresponding to the 85 kDa truncated form of PARP is observable by Western blot. This band is usually absent or weak if the cells are untreated, so the only observable band is the 110 kDa band.
“++” means that the band corresponding to the 85 kDa truncated form of PARP is clearly observable on Western blot. The uncut band (110 kDa) usually coexists with the cut band.
“++++” means PARP cut almost completely. The 100 kDa band often disappeared due to the 85 kDa form.
アポトーシス核の特徴
「+」とは、DAPI染色後、少数の凝縮又は断片化された核が観察可能であることを意味する。
「++」とは、DAPI染色後、多数の凝縮又は断片化された核が観察可能である(20〜50%)ことを意味する。
「+++」とは、核のほとんどが凝縮又は断片化していることを意味する。
Characteristics of apoptotic nuclei “+” means that a small number of condensed or fragmented nuclei can be observed after DAPI staining.
“++” means that a large number of condensed or fragmented nuclei are observable (20-50%) after DAPI staining.
“++++” means that most of the nuclei are condensed or fragmented.
Claims (18)
式中、
Y1、Y2は−N=C−であり;
Ar1、Ar2はそれぞれ独立して、C6〜C10アリール又は5〜7員ヘテロアリールから選択され、前記アリール及びヘテロアリール基は、場合により1〜3個のR3基で置換され、但し:
− Ar1、Ar2の両方を、4−ピリジル、非置換2若しくは3−チオフェニル、又は3,4−ジメトキシフェニル、又は3,4,5−トリメトキシフェニルで表されるものと同一とすることはできず、
i及びjは独立して0又は1であり、但し:
− i+j≧1であり、且つ
− Y1、Y2のいずれも−S−でないときに、i+j=2であり;
R1、R2はそれぞれ独立して、C1〜C6アルキル、C6〜C10アリール、(C6〜C10)アリール(C1〜C6)アルキル、(C6〜C10)アリール(C2〜C6)アルケニル、(C6〜C10)アリールカルボニル、(C6〜C10)アリール(C1〜C6)アルキルカルボニル、C(=O)H、COOH、OHから選択され、前記アルキル基は場合によりOHで置換され;
k及びlは独立して0、1であり;
R3はそれぞれ独立して、C1〜C6アルキル、C1〜C6アルコキシ、OH、C(=O)H、(CH2)nCO2H、(CH2)pCN、(CH2)qC(=N(OH))NH2、I、Cl、Br、F、C6〜C10アリール、および5〜7員ヘテロアリール、(C6〜C10)アリール(C1〜C6)アルキル、(C6〜C10)アリール(C2〜C6)アルケニルから選択され、前記アルキル基は場合によりOHで置換され;
nは0、1、2、3であり;
pは0、1、2、3であり;
qは0、1、2、3であり;
以下の化合物を除く:
2−(ピリジン−3−イル)−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン、
3−(5−メチル−6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン、
3−(6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン。 A pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof mixed with at least one pharmaceutically acceptable excipient or carrier:
Where
Y 1 and Y 2 are —N═C—;
Ar 1 and Ar 2 are each independently selected from C 6 -C 10 aryl or 5-7 membered heteroaryl, said aryl and heteroaryl groups optionally substituted with 1 to 3 R 3 groups; However:
-Ar 1 and Ar 2 are both identical to those represented by 4-pyridyl, unsubstituted 2 or 3-thiophenyl, or 3,4-dimethoxyphenyl, or 3,4,5-trimethoxyphenyl. Cannot
i and j are independently 0 or 1, provided that:
I + j ≧ 1, and when neither Y 1 nor Y 2 is −S−, i + j = 2;
R 1 and R 2 are each independently C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkyl, (C 6 -C 10 ) aryl. (C 2 -C 6 ) alkenyl, (C 6 -C 10 ) arylcarbonyl, (C 6 -C 10 ) aryl (C 1 -C 6 ) alkylcarbonyl, C (═O) H, COOH, OH The alkyl group is optionally substituted with OH;
k and l are independently 0, 1;
Each R 3 is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, C (═O) H, (CH 2 ) n CO 2 H, (CH 2 ) p CN, (CH 2 ) q C (= N (OH )) NH 2, I, Cl, Br, F, C 6 ~C 10 aryl, and 5-7 membered heteroaryl, (C 6 ~C 10) aryl (C 1 -C 6 ) Alkyl, (C 6 -C 10 ) aryl (C 2 -C 6 ) alkenyl, wherein said alkyl group is optionally substituted with OH;
n is 0, 1, 2, 3;
p is 0, 1, 2, 3;
q is 0, 1, 2, 3;
Excluding the following compounds:
2- (pyridin-3-yl) -5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) pyridine,
3- (5-methyl-6- (5-methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine,
3- (6- (5-Methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine.
式中、
X1、X2はそれぞれ独立して、C又はNから選択され、
R1、R2、R3はそれぞれ独立して、請求項1〜8のいずれか1項に定義される通りである。 9. A pharmaceutical composition according to any one of claims 1 to 8, selected from compounds of formula (Ia):
Where
X 1 and X 2 are each independently selected from C or N;
R 1 , R 2 , R 3 are each independently as defined in any one of claims 1-8.
− 5,6’−ジ(ピリジン−3−イル)−5’−メチル−3−((E)−スチリル)−2,3’−ビピリジン、
− 5,6’’−ジ(ピリジン−3−イル)−3,5’’−ビス−((E)−スチリル)−[2,3’;6’,3’’]ターピリジン、
− 3,5’’,5’’−トリメチル−5,6’’−ジフェニル−[2,3’;6’,3’’]−ターピリジン、
− 5’−ブロモ−3’,5−ジメチル−6−(3−メチル−4−ピリジン−3−イルフェニル)−3,2’−ビピリジン、
− 5’−(2−メチル−4−ピリジン−3−イルフェニル)−3’,5−ジメチル−6−(2−メチル−4−ピリジン−3−イルフェニル)−3,2’−ビピリジン、
− 2−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)−5−フェニル−3−スチリルピリジン、
− 2−(5−メチル−6−フェニルピリジン−3−イル)−5−(ピリジン−3−イル)−3−スチリルピリジン、
− 5−(3−ベンジルピリジン−2−イル)−2−(5−ベンジルピリジン−3−イル)ピリジン
から選択される、請求項1〜9のいずれか1項に記載の医薬組成物。 The compound of the formula (I) is
-5,6'-di (pyridin-3-yl) -5'-methyl-3-((E) -styryl) -2,3'-bipyridine,
5,6 ″ -di (pyridin-3-yl) -3,5 ″ -bis-((E) -styryl)-[2,3 ′; 6 ′, 3 ″] terpyridine,
3,5 ″, 5 ″ -trimethyl-5,6 ″ -diphenyl- [2,3 ′; 6 ′, 3 ″]-terpyridine,
-5'-bromo-3 ', 5-dimethyl-6- (3-methyl-4-pyridin-3-ylphenyl) -3,2'-bipyridine,
-5 '-(2-methyl-4-pyridin-3-ylphenyl) -3', 5-dimethyl-6- (2-methyl-4-pyridin-3-ylphenyl) -3,2'-bipyridine,
-2- (5-methyl-6- (pyridin-3-yl) pyridin-3-yl) -5-phenyl-3-styrylpyridine,
-2- (5-methyl-6-phenylpyridin-3-yl) -5- (pyridin-3-yl) -3-styrylpyridine,
10. The pharmaceutical composition according to any one of claims 1 to 9, selected from 5- (3-benzylpyridin-2-yl) -2- (5-benzylpyridin-3-yl) pyridine.
式中、
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、lは請求項1に定義される通りであり、
但し、k=l=1であるとき:
− R1、R2のうち少なくとも1つがHとは異なり;及び
− R1、R2の一方がCH3であれば、他方はHまたはCH3ではなく、
以下の化合物を除く:
− 2−(ピリジン−3−イル)−5−(5−(ピリジン−3−イル)−3−スチリルピリジン−2−イル)ピリジン、
− 3−(5−メチル−6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン、
− 3−(6−(5−メチル−6−(ピリジン−3−イル)ピリジン−3−イル)ピリジン−3−イル)ピリジン。 Compounds of formula (I) and their pharmaceutically acceptable salts:
Where
Y 1 , Y 2 , Ar 1 , Ar 2 , R 1 , R 2 , i, j, k, l are as defined in claim 1,
However, when k = l = 1:
- at least one of R 1, R 2 is different from the H; and - R 1, if one is CH 3 of R 2, the other is not H or CH 3,
Excluding the following compounds:
-2- (pyridin-3-yl) -5- (5- (pyridin-3-yl) -3-styrylpyridin-2-yl) pyridine,
-3- (5-methyl-6- (5-methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine,
3- (6- (5-Methyl-6- (pyridin-3-yl) pyridin-3-yl) pyridin-3-yl) pyridine.
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VOISIN-CHIRET A S; BOUILLON A; BURZICKI G; CELANT M; LEGAY R; EL-KASHEF H; RAULT S: "A GENERAL SYNTHESIS OF HALO-OLIGOPYRIDINES. THE GARLANDING CONCEPT", TETRAHEDRON, vol. VOL:65, NR:3, JPN5017001823, 17 January 2009 (2009-01-17), NL, pages PAGE(S):607 - 612 * |
VOISIN-CHIRET A S; MURAGLIA M; BURZICKI G; PERATO S; CORBO F; ET AL: "SYNTHESIS OF NEW PHENYLPYRIDYL SCAFFOLDS USING THE GARLANDING APPROACH", TETRAHEDRON, vol. VOL:66, NR:40, JPN5017001825, 2 October 2010 (2010-10-02), NL, pages PAGE(S):8000 - 8005 * |
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